HU211840A9 - Antibiotic compounds - Google Patents

Description

The present invention relates to carbapenern derivatives. more particularly carbapenem derivatives having a phenyl substituted by a carboxyl group. as well as the pharmaceutical compositions which teach them as an active ingredient. The present invention also relates to a process for the preparation of novel carbapenem derivatives and to pharmaceutical compositions for teaching them. The present invention also relates to intermediates useful in the preparation of novel carbapenem derivatives. and the use of novel carbapenem derivatives for medical purposes.

The compounds of the present invention possess antibiotic activity and are accordingly useful in the treatment of all bacterial diseases which can be treated with antibiotics, including bacterial diseases of mammals, such as humans.

Kabapenem compounds were first isolated from fermentation broths in 1974. Isolation derivatives have been shown to be broad spectrum antibiotic agents. From this point on, extensive research has begun to produce novel carbapenem derivatives; there are hundreds of patents and scientific publications on the subject.

The first, and only one, commercially available carbapenem compound is N-formimidoillienamycin (imipenem). which has a broad spectrum antibacterial effect.

The compounds of the present invention have a broad spectrum antibacterial activity and are Gram positive and Gram positive. as well as aerobic and anaerobic bacteria. The compounds are sufficiently stable against β-lactamases. Some of the compounds have very favorable activity.

In the specification and claims, carbapenem derivatives are referred to according to a semi-systematic nomenclature generally accepted in the art: the numbering of the carbapenem backbone is illustrated in formula (a).

The present invention relates to compounds of formula (I). and pharmaceutically acceptable salts and esters thereof which can be hydrolysed in vivo.

R ^{J is} 1-hydroxyethyl. 1-fluoroethyl or hydroxymethyl.

R ^{2 is} hydrogen or C 1-4 alkyl.

R ^? represents a hydrogen atom or a C 1-4 alkyl group. and

R ⁴ and R ² are each independently hydrogen. halo. cyano. C 1-4 alkyl. nitro. hydroxy, carboxyl, C 1-4 alkoxy. (C 1 -C 4 alkoxy) carbonyl. aminosulfonyl. (C 1 -C 4 alkyl-1-aminosulfonyl-dili-C 4 alkyl-1-amino-sulfonyl, carbamoyl (C 1 -C 4 -alkyl) -carbamoyl-di (C 1 -C 4) -alkylcarbamoyl- , trifluoromethyl, sulfonic acid, amino (C 1-4 alkyl) amino, di (C 1-4 alkyl) amino, (C 1-4 alkanoyl) amino (1-4). (C 1 -C 4 alkanoyl) - (N 1 -C 4 alkyl) amino or C 1 -C 4 alkanesulfonamido or (C 1 -C 4 alkyl) -S (O) _n - wherein n is 0, 1 or 2, with the proviso that no hydroxyl or carboxyl substituent is attached to the phenyl ring at the ortho position relative to the -NR ³ - group.

As used herein and in the claims, the term "alkyl" refers to both straight and branched chain groups. The alkyl group may be, for example, methyl, ethyl, npropyl, isopropyl, n-bulyl or isobutyl.

Preferably R ^{1 is} 1-hydroxyethyl.

R ^{2 is} hydrogen or C 1 -C 4 alkyl, such as methyl, ethyl, η-propyl, isopropyl or n-butyl. Preferably R ^{2 is} hydrogen or methyl, most preferably melyl.

R ^{3 is} hydrogen or C 1-4 alkyl. for example methyl. ethyl, n-propyl. isopropyl or n-butyl esopurt. R 'is preferably hydrogen,

R ⁴ and R ⁵ may be the same or different and the following atoms or groups may represent: hydrogen: halogen. such as fluorine, bromine or chlorine; CN; C 1-4 alkyl. such as methyl. ethyl, n-propyl. isopropyl or nbulyl: nitro. hydroxy group: carboxyl group: C1-C4 alkoxy. For example, methoxy or ethoxy: (C 1 -C 4 alkoxycarbonyl. e.g. methoxycarbonyl-ethoxycarbonyl or n-propoxycarbonyl: amtosulfonyl) (C 1 -C 4 alkyl-aminosulfonyl). such as methylaminosulphonyl or ethylaminosulphonyl; di- (C 1-4 alkyl t-aminosulphonyl) such as dimethylaminosulphonylmethyl-ethylaminosulphonyl or diethylaminosulphonyl; C 1-4 -alkyl (carbamoyl) such as methylcarbamoyl or ethylcarbamoyl: di- (C 1-4 -alkyl) carbamoyl such as dimethylcarbamoyl or diethyl-; carbamoyl; trifluoromethyl: sulfonic acid; amino: (C1-C4-alkyl-t-amino) such as methylamino or ethylamino: di-G4-alkylalkylamino such as dimethylamino or diethylamino: (C 1-4 alkanoyl) amino such as acetamido or propionamido (C 1-4 alkanoyl) - (N- / C 1-4) alkyl (N) -amino, such as N-methylacetamido: 1- (S) -N-alkanesulfonamido. Thus, the methanesulfonamido group. and (1-4C) alkyl-S (O) - - such as methylthio. methylsulfinyl or methylsulfonyl.

A preferred group of compounds of formula (I) are those wherein R ^J and R ⁵ are each independently hydrogen litter. fluoro. chlorine or hydroxyl, carboxyl. cyano. nitro. methyl-. ethyl, methoxy. ethoxy. methoxycarbonyl. carbamoyl. methylcarbamoyl. dimethylcarbamoyl. trifluoromethyl-. sulfonic acid. methylsulfinyl, methylsulfonyl. methanesulfonamido or acetamido.

HU 211 840 A9

R ⁴ and R ⁵ may each be a substituent other than hydrogen, but compounds of formula I in which at least one of R ⁴ and R ⁵ is hydrogen are usually preferred.

Particularly preferred compounds of formula I are those wherein R ^{4 is} hydrogen, fluoro, chloro or carboxyl, methyl, methoxy, cyano, sulfonic acid, or methoxycarbonyl, while R ^{5 is} hydrogen.

The present invention encompasses all epimeric, diastereoisomeric, and tautomeric forms of the compounds of formula I, the absolute configuration of which is represented by the formula (I) at position 5. Bonded bonds in the formulas mean that in a three-dimensional representation, the corresponding bond protrudes from the plane of the paper, whereas in dashed lines, bonded means that in the three-dimensional representation, the corresponding bond points behind the plane of the paper. Compounds of formula (I) may have several asymmetric centers other than the 5-position asymmetry; For example, the 1-hydroxyethyl and 1-fluoroethyl group at R ¹ also contain an asymmetric center; an additional asymmetric center is in position 6; when R ^{2 is C} 1 -C 4 alkyl, position 1 is also an asymmetric center; in addition, the pyrrolidine ring represented by formula (II) contains asymmetric triacenyl at positions 4 'and 2'.

Preferred are compounds of formula 11j. in which the protons of the β-lactam ring are in a trans configuration relative to one another. When R11 is ¹ -hydroxyethyl or 1-fluoroethyl, the substituent at the 8-position may preferably be in the R configuration. Accordingly, a preferred group of compounds of formula I are those of formula III wherein R ^{2 is} . R \ R ⁴ and R ^s are as defined above -. and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.

Of the compounds of formula (I) wherein R ² is C 1 -C 4 alkyl (e.g., methyl), the R-configuration at position 1 is preferred.

Further preferred are those compounds of formula (I). wherein the pyrrolidine ring is substituted at the 2 'and 4' positions in the absolute configuration shown in formula (b).

A preferred group of compounds of the present invention are compounds of formula IV wherein R 1 is. R ⁴ and R ⁵ are as defined above, and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.

Particularly preferred compounds of formula IV are those wherein R ^{3 is} hydrogen and R ⁴ and R ⁵ are each independently hydrogen, fluoro. chlorine or hydroxy, carboxyl, cyano, nitro, methyl, ethyl, methoxy. ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl. dimethylcarbamoyl, methanesulfonyl, trifluoromethyl. sulfonic acid, methylsulfinyl, methanesulfonamido or acetamido.

Particularly preferred are compounds of formula IV wherein R ³ and R ⁵ are both hydrogen and R ^{4 is} hydrogen, carboxyl, fluoro, chloro, methyl, methoxy, cyano, sulfonic acid, or methoxycarbonyl.

Pharmaceutically acceptable salts of the compounds of formula I include, for example, acid addition salts such as hydrochlorides, hydrobromides, citrates, maleates, and salts with sulfuric acid and phosphoric acid. Another group of pharmaceutically acceptable salts are salts with pharmaceutically acceptable bases, such as alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), organic amines (such as triethylamine, morpholine, N-methylpiperidine). salts with piperidine, procaine, dibenzylamine, or Ν, Ν-dibenzylelylamine), and salts with amino acids such as lysine. These salts are one depending on the number of carboxyl groups in the compound of formula (I) and the valence of the salt-forming cation. may contain two or three salt-forming cations.

Pharmaceutically acceptable salts of the compounds of formula (I) include sodium and potassium salts. However, in the preparation of compounds of Formula I, it is desirable to employ a salt-forming ion which forms a salt which is poorly soluble in the solvent used, whether or not it is pharmaceutically acceptable.

The term "esters that can be hydrolyzed under carrier conditions" refers to pharmaceutically acceptable esters which are released from the parent compound by hydrolysis in the human body. That one. whether or not an ester can be hydrolyzed under in vivo conditions. for example, it may be determined by administering the test ester to laboratory animals (e.g., intravenously) and then examining the body fluids of the animals for the presence of the parent compound. In vivo hydrolysable esters formed on the carboxyl group include, for example, (C 1 -C 6) alkoxy-methyl esters. such as methoxymethyl esters; C 1-6 alkanoyloxy methyl esters such as pivaloyloxymethyl esters; phthalidyl esters; (C3-C6 cycloalkoxy) carbonyloxy (C1-C6 alkyl) esters. Thus, 1- (cyclohexyloxycarbonyloxy) ethyl esters; 1,3-dioxolen-2-onylmethyl esters such as 5-methyl-1,3-dioxolen-2-onylmethyl esters; and (C 1 -C 6) alkoxy-carbonyloxyethyl esters, such as 1- (methoxycarbonyloxy) ethyl esters. Such esters may be formed on any carboxyl group of the compounds of formula (I). Examples of in vivo hydrolysable esters of hydroxyl include acetyl, propionyl, pivaloyl, phenylacetyl and (C1-C4) alkoxy-carbonyl (such as ethoxycarbonyl) esters.

Examples of compounds of the invention include:

(LR, 5S.6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-5-hydroxy-phenyl-3

EN 211 840 A9 Carbamoyl-pyrrolidin-4-yl-lio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3-carboxylic acid.

(5 S, 6S.8R, 2'S, 4'S) -2- (2- / 3-carboxy-4-chloro-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) - 1-methyl) -carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-chloro-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (IR, 5S.6S.8R.2'S.4'S) -2- (2- / 3-Carboxyphenylcarbamoyl) - Pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S.6S.8R, 2'S, 4'S) -2- (2/3) -carboxy-6- (methanesulfonyl) -phenylcarbamoyl-pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid, (1R, 5S , 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-4-fluoro-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) -1-methyl- carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6-fluoro-phenylcarbanoyl) -pyrrolidin-4-yl-thi o ) -6- (1-Hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid.

11R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- (3-Carboxy-2,4-difluorophenylcarbamoyl / pyrrolidin-4-ylthio) -6-11-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, <1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3,4-Dicarboxyphenylcarbamoyl / pyrrolidin-4-yl-thio) -6- (1-Hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid.

R.5S.6S.8R. 2'S, 4'S) -2- (2- [3-Carboxy-4-hydroxy-phenyl] -carbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3- carboxylic acid.

t] R.5S.6S.8R.2'S.4'S) -2- [2- (3,5-Dicarboxyphenylcarbamoyl / pyrrolidin-4-yl-lio) -6- (1-hydroxy-ethyl) -1 methylcarbapenem-3-carboxylic acid.

(IR.5S.6S.8R.2'S.4'S) -2- (2- [2-Carbamoyl-3-carboxylenylcarbamoyl] -pyrrolidin-4-yl-lio) -6- (1-hydroxy-ethyl) -1 -Methyl-carbapenem-3-carboxylic acid.

(LR.5S.6S.8R.2'S.4'S) -2- (2- / 3-carboxy-4-carbamoylphenyl-carbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) 1 kurbapenem-methyl-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-5-carbamoyl) -enylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy) ethyl) 1-methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-5-acetamidophenyl-carbamoyl) -pyrrolidin-4-yl-thio ) -6- (1-Hydroxyethyl) 1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3-Carboxy-4-acetamidolenylcarboxylate) Nioyl-pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3-carboxylic acid.

(5 S, 6S.8R, 2'S, 4'S) -2- (2- / 3-carboxy-5- (methylsulfonyl) sulphonamido) phenyl-carbamoyl / pyrrolidin-4-ylthio) -6- ( hydroxy-ethyl) -l-methylcarbapenem-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-sulfo-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-carbamoyl-phenylcarbamoyl] -pyrrolidin-4-yl-thio) - 6- (1-Hydroxyethyl) 1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-2- (dimethylamino) carbonyl) phenylcarbamoyl (pyrrolidin-4-ylthio) -6- (hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (5R.6S.8R.2'S.4'S) -2- ( 2- (3-Carboxyphenylcarbamoyl / pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) -carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S ) -2- (2- [3-Carboxy-4-methyl-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3-carboxylic acid, ( 1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-5-methylphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1 -methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S.8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6-methyl-phenylcarbamoyl / -pyrrolidin-4-yl-thio) -6 - (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S.4'S) -2- (2- / 3-k) arboxy-2-methoxyphenylcarbamoyl (pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarboxylic acid non-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S , 4'S) -2- (2- [3-Carboxy-4-methoxyphenylcarbamoyl] -pi) Tolidin-4-yl-lio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3- carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-methoxyphenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy) ethyl) -1-methylcarbapenem-3-carboxylic acid, (IR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6-methoxyphenyl) carbamoyl / pyrrolidine-4 -yl-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid,

() R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-4,6-dimethoxyphenylcarbamoyl] -pyrrolidin-4-yl] thio) -6- (1-hydroxy) ethyl) 1-methylcarbapenem-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-5- (methoxycarbonyl) -phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1 -hydroxyethyl) -l-methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-5-cyano-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (IR.5S.6S.8R.2'S.4'S) -2- (2- / 3-Carboxy-5-trifluoromethyl) -phenylcarbamoyl / -pinOlidin-4 -yl-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3-carboxy-4, 6-Difluorophenylcarbamoyl (pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6- (methylsulfinyl) phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1 -hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-5- (methylsulfonyl) phenyl) - carbamoyl / pyrrolide η-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid.

(LR.5S.6S.8R.2'S, 4'S) -2- (2- / 3-carboxy-5-fluoro-phenylcarbamoyl / pyrrolidin-4-yl-lio) -6- (l-hydroxyethyl) - l-methyl-carbapenem-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-cyano-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-N'-methyl-phenylcarbamoyl / -pyrrolidin-4-yl-thio) -6- (1-Hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, and pharmaceutically acceptable salts and esters thereof which can be hydrolysed in vivo.

Particularly preferred compounds of the invention are:

(1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-methyl-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-methyl-carbapenem-3-carboxylic acid,

HU 211 840 A9 (1R, 5S, 6S, 8R, 2'S.4'S) -2- (2- [3-Carboxy-5-methoxyphenylcarbamoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxy) ethyl) -1-bis-1-carboxylic acid non-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-methoxy-phenylcarbamoyl] -pyrrolidine-4 -ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy) 5- (methoxycarbonyl) phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S.8R) , 2'S, 4'S) -2- (2- / 3-carboxy-5-cyano-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) -l-methyl-carbapenem-3-carboxylic acid , (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-chloro-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methylcarbapenem-3-carboxylic acid,

() R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxyphenylcarbamoyl / pyrrolidine-4-ylthio) -6- (1-hydroxyethyl) - 1-methylcarbapenem-3-carboxylic acid.

(LR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-4-fluoro-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) - l-methyl-carbapenem-3-carboxylic acid.

(IR, 5S, 6S.8R.2'S, 4'S) -2- (2- / 3-carboxy-6-fluoro-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) - 1-methyl-carbapenem-3-carboxylic acid.

(1R, 5S, 6S, 8R, 2'S, 4'5) -2- (2- / 3,4-Dicarboxyphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxy) ethyl) -1-methylcarbapenem-3-carboxylic acid.

(R 5S, 6S, 8R, 2S, 4S) -2- (2- [3,5-Dicarboxyphenylcarbamoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxy-ethyl) -1- methylcarbapenem-3-carboxylic acid.

(LR.5S.6S, 8R.2'S.4'S) -2- (2- / 3-carboxy-5-sulfo-phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) - 1-methylcarbapenem-3-carboxylic acid, and pharmaceutically acceptable salts thereof.

The compounds of formula IIi, as well as their pharmaceutically acceptable salts and in vivo hydrolysable esters thereof, are commonly used in the pharmaceutical treatment of mammals, including humans, for the treatment of infections. The pharmaceutical compositions are prepared by known methods of pharmaceutical technology.

The present invention relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof together with a pharmaceutically acceptable carrier, diluent and / or other excipient.

The pharmaceutical compositions may be administered to patients in need of treatment by conventional means such as oral, rectal or parenteral administration. For therapeutic purposes, the active compounds may be formulated in conventional pharmaceutical forms such as tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories or sterile injectable aqueous or oleaginous solutions or suspensions.

The compounds of the present invention may also be marketed as powder formulations containing the active ingredient as a single component or as a dry powder mixture with other components. For example, the acidic active compounds may be mixed with alkali metal carbonates or bicarbonates in the dry state. The compounds of the invention may also be used in the form of freeze-dried compositions which may contain the active ingredient as a single component or in admixture with conventional excipients. Pharmaceutical excipients include, for example, structuring agents, anti-freeze agents, and pH modifiers, such as mannitol, sorbitol, lactose. glucose, sodium chloride, dextran, sucrose, mailose. gelatin, bovine serum albumin, glycine, mannose, ribose, polyvinylpyrrolidone, cellulose derivatives, glutamine. inositol, potassium glutamate, erythritol, serine and other amino acids; and buffering agents such as dipotassium hydrogen phosphate and potassium citrate.

The pharmaceutical compositions of the present invention may optionally contain or be co-administered with one or more other known active ingredients in addition to those of the present invention. Other therapeutic agents include, but are not limited to, other clinically useful bacterial agents (e.g., other β-lactams or aminoglycosides), β-lactamase inhibitors (such as clavulanic acid. substances (such as dehydropeptidase inhibitors such as Z-2- (acylamino) -3-substituted-propenoic acid esters, including cilastatin) and Nacylated amino acids (such as those disclosed in European Patent Application 178,911). compounds).

The pharmaceutical compositions are preferably oral dosage units, such as tablets or capsules, which are 100 mg / g unit dose. they may contain the active ingredient of the invention.

A particularly preferred class of pharmaceutical compositions is intravenous, subcutaneous or intramuscular injections, e.g. sterile injectable compositions containing the active ingredient of the invention.

The following are examples of the composition of the pharmaceutical compositions of the present invention:

/. preparation: Example 1 Preparation 2: 50 mg Example 1 50 mg glycine 31 mg These compositions are prepared by: a

A 1% by weight aqueous solution of the components is freeze-dried. Prior to use, the powder formulation is diluted with 0.9% w / w aqueous sodium chloride solution to the desired active ingredient content (preferably 1-10 mg / ml active ingredient).

The formulations are prepared using the compounds 2-37 instead of the compound of Example 1. Any of Examples 1 to 4 may also include a serinyl compound.

HU 211 840 A9

The pharmaceutical compositions of this invention are usually administered in human medicine in a manner similar to imipenem for the treatment of bacterial infections. It will be appreciated by those skilled in the art that the precise dosage required for treatment will vary with the potency and duration of action of the particular compound. In the case of intravenous, subcutaneous or intramuscular administration to patients, it is usually 0.105-5 g / day. preferably, 0.12.5 g of active ingredient per day is administered, optionally in 2-4 daily portions. Bolus injection may also be used for intravenous, intramuscular or subcutaneous administration. Intravenous treatment can also be accomplished by continuously infusing the patient for a defined period of time. However, the treatment may also be administered orally; in this case, the daily dose may be substantially the same as the daily dose for parenteral treatment. Thus, for oral administration, the active ingredient is usually administered at a daily dose of 0.05-5 g; this amount of the active ingredient can be delivered to the body at once or divided into 2 to 4 daily portions.

Compounds of formula (1). as well as hydrolyzable esters can be prepared according to the present invention, pharmaceutically acceptable salts and in vivo that the compounds of formula (V): - wherein R ^2, R ⁴ and R ⁵ are as defined above, but R ^J, and R ⁵ groups, optionally protecting groups may be attached.

-COOR ⁶ and -COOR ^{7 represent a} carboxyl group or a protected carboxyl group.

R ⁵ has the same meaning as R ^? report. or R ^{8 is a} protecting group.

R ^{9 is} hydrogen or an amino protecting group. and

R ¹⁰ is as defined for R ¹ , or R ^{10 is a} protected 1-hydroxyethyl or protected hydroxymethyl group.

with the proviso that the compound of formula VI has at least one protecting group deprotected and / or protected, and optionally the resulting product is converted into a pharmaceutically acceptable salt or ester which can be hydrolyzed in vivo.

As protecting groups, any suitable protecting group may be used. Such groups and methods for their introduction are well known in the art.

The protecting groups may be removed by methods well known in the art or well known to those skilled in the art. In each case, a suitable method for removing the protecting groups is employed. which damages other parts of the molecule to a minimum.

The starting materials of formula (V) are new. Also included are compounds of formula (V).

The following examples of protecting groups on compounds of Formula V1 are provided, but are not exhaustive (exemplary "short chain" refers to 1-4 carbon atoms). Occasionally, some examples of the deprotection of protecting groups are given. .

Protective groups that may be added to the carboxyl groups include, for example, residues of ester-forming aliphatic or araliphatic alcohols or ester-forming silanols. The ester-forming alcohols or silanols preferably contain from 1 to 20 carbon atoms.

Examples of protecting groups that may be added to the carboxyl groups are: straight or branched C 1 -C 12 alkyl groups (such as isopropyl or tert-butyl), lower alkoxy (lower alkyl) moieties (such as meloxymethyl, ethoxymethyl or isobutoxy). lower aliphatic acyloxy (lower alkyl) groups (such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl). lower alkoxycarbonyl 1-oxy (lower alkyl (such as 1-methoxycarbonyloxy-ethyl or 1-ethoxycarbonyloxy / ethyl), aryl (lower alkyl) (e.g. p-methoxybenzyl, ο-nitrobenzyl, p-methylbenzylbenzhydryl and phthalidyl), tri- (lower alkylsilyl) groups (such as trimethylsilyl and tert-butyldimethyl). tri-lower alkyl-syphyl (lower-alkyl (such as trimethylsilyl-ethyl) soport) and C2-C6 alkenyl groups (such as allyl and vinyl ethyl).

A particularly preferred method of removing the carboxyl protecting groups is acid-, base-, metal- or enzyme-catalyzed hydrolysis.

Examples of protecting groups that may be added to the hydroxy group include lower alkenyl groups (such as allyl). lower alkanoyl groups (such as acetyl). lower alkoxycarbonyl groups (such as tert-butoxycarbonyl). hydrocarbyl groups such as allyloxycarbonyl (such as allyloxycarbonyl). aryl (lower alkoxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl); tri (lower alkyl 1-silyl groups (such as trimethylsilyl and tert-butyldimethylsilyl) and aryl lower alkyl 1 (such as benzyl).

Examples of protecting groups which may be added to the amino group include formyl, aralkyl groups (such as benzyl and substituted benzyl groups such as p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, triphenylmethyl), di p-anisyl-methyl. furylmethyl, lower alkoxycarbonyl (such as tert-butoxycarbonyl), lower alkenyloxycarbonyl (such as allyloxycarbonyl), aryl (lower alkoxycarbonyl) (such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl and p-nitrobenzyloxycarbonyl), trialkylsilyl groups (such as trimethyl) silyl and tert-butyldimethylsilyl), alkylidene groups (such as methylidene), benzylidene and substituted benzylidene groups.

The protecting groups on the hydroxyl and amino groups may be removed, for example, by acid, base, metal or enzyme-catalyzed hydrolysis. P-nitrobenzyloxycarbonyl and related groups

I

By hydrogenolysis, the o-nitrobenzyloxycarbonyl group and related groups can also be removed photolytically.

Preferred protecting groups for the carboxyl and hydroxyl groups of the compounds of formula I are allyl and apnitrobenzyl. The allyl group is preferably cleaved by a palladium catalyzed reaction; as a catalyst, for example, tetrakis (triphenylphosphine) palladium in the presence of Meldrum acid. The reaction medium may be a mixture of tetrahydrofuran and a dipolar aprotic solvent such as dimethylsulfoxide and tetrahydrofuran or a mixture of 1,3-dimethyl-2-oxo-tetrahydropyrimidine and tetrahydrofuran or an alcohol and tetrahydrofuran such as isopropanol and tetrahydrofuran or a mixture of ethanol and tetrahydrofuran. The reaction is preferably carried out at room temperature. Instead of Meldrum acid, methylaniline can also be used in dichloromethane. When a sodium salt such as 2-ethylhexanecarboxylic acid is added to the reaction mixture, the reaction mixture is in the form of its sodium salt. the desired product precipitates out.

The p-nitrobenzyl group is preferably removed by hydrogenolysis in the presence of palladium catalyst.

The invention further relates to a process for the preparation of compounds of formula (I) and (V) by:

a) reacting a compound of formula VI with a compound of formula VII wherein R ² and R ^{4 are} -R ^{, w} is as defined above, and L is a leaving group; or

b) cyclizing the compounds of formula (VIII) wherein R ¹ and R ⁴ -R ¹⁰ are as defined above and R ¹¹ , R ¹² and R ¹¹ 'are independently C 1-6 alkoxy, anyloxy. - (C 1 -C 6 alkyl) amino or diarylamino, or two of them form o-phenylene dioxy, or R ". One of R ¹² and R ¹³ is (C 1 -C 4) alkyl allyl. while the remaining two substituents are independently C 1-4 alkyl, trifluoromethyl or phenyl, and any of the abovementioned substituents is optionally C 1-3 alkyl or C 1-3 and any of the reactive groups in the compound of formula (VIII) may be optionally protected, and if necessary, (i) the optional protecting group (s) removed.

(ii) converting the product into a pharmaceutically acceptable salt, and / or (iii) converting the product to an ester that can be hydrolyzed under in vivo conditions.

In the compounds of formula (VI), L is preferably a reactive ester group formed on a hydroxy group, such as a sulfonate group (such as C 1-6 alkanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy). groups). a phosphoric ester group (such as a diarylphosphoric ester group such as a diphenylphosphoric ester group) or a halogen atom (e.g. a chlorine atom). However, L may also be an easily cleavable sulfoxide group such as -SOCH = CH-NHCOCH ₃ . In the compounds of formula (VI), L is preferably di Γόη il - main phosphoric acid ester (-OP / O / OPh / ₂ ).

Compounds of formula (VI) and their preparation are described in detail in the literature of carbapenem compounds (see, for example, European Patent Nos. 126,587, 160,391,243,686 and 343,499).

The compounds of formula (VI) are usually reacted with compounds of formula (VII) in the presence of a base. Examples of the base include organic amines. For example, diisopropylethylamine or inorganic bases such as alkali metal carbonates (e.g. potassium carbonate) can be used. The reaction is usually carried out at a temperature between -25 ° C and room temperature, preferably at about -20 ° C. The reactions are usually carried out in the presence of an organic solvent such as acetonitrile or dimethylformamide. The reaction conditions are usually substantially the same as those described in the literature.

The compounds of formula (VII) are novel. Our invention extends to the compounds of formula VII and their preparation.

Compounds of formula (VII) may be prepared by reacting a compound of formula (IX) wherein R ⁴ -R ⁶ , R ⁸ and R ⁹ are as defined above and R ^{14 is a} protecting group such as C 1-6 alkanoyl. (C 1 -C 6 alkoxy) carbonyl or benzoyl group is deprotected. Preferably R ^{14 is} acetyl or tert-butoxycarbonyl. Compounds of formula (IX) may be converted to compounds of formula (VII) by known deprotection methods; For example, the acetyl group may be removed by alkaline hydrolysis in aqueous alkanol or alkenol (e.g. allyl alcohol)

The compounds of formula IX are novel. Our invention extends to the compounds of formula IX and their preparation.

Compounds of formula (IX) may be prepared as follows. by reacting a reactive derivative of a compound of formula (X) which may be formed in the reaction mixture itself with a compound of formula (XI): wherein R ⁴ -R ⁶ , R ^s . ^TJ R and ^R14 are as defined above. Reactive derivatives of compounds of formula (X) include, for example, acid halides. acid anhydrides and reactive esters such as 1H-benzo [1,2,3] triazol-1-yl, pentafluorophenyl and 2,4,5-trichlorophenyl. and a benzimidazol-2-yl ester of a lyocarboxylic acid of formula (X). The reaction is carried out under known conditions. For example, compounds of formula (X) may be reacted with compounds of formula (XI) in the presence of a Vilsmeier reagent (which forms a desired reactive derivative of compounds of formula (X) in the reaction mixture). The reaction temperature may range from -30 ° C to 25 ° C, preferably from -20 ° C to 5 ° C.

Compounds of formula (X) and (XI) are known to those skilled in the art, for example, as described in the Examples herein. European Sun.

The process of the present invention can be prepared by the methods described in the patent specification, or similarly.

In the compounds of formula (VIII), R ¹¹ , R ¹² and R ¹³ are each independently preferably C 1-6 alkoxy (e.g. methoxy, ethoxy, isopropoxy, n-propoxy or n-butoxy), aryloxy group. (e.g., optionally substituted phenoxy), di- (C 1 -C 6) alkylamino (e.g. dimethylamino or diethylamino) or diarylamino (e.g. diphenylamino), or any two of them may be taken together to form an o-phenylene dioxide group. Preferably R ¹¹ . R ¹² and R ^1? they are the same and are preferably C1-C6 alkoxy (e.g. methoxy, ethoxy, isopropoxy or n-butoxy) or phenoxy.

Compounds of formula (VIII) are cyclized under standard conditions known in the art to compounds of formula (V). We usually do this. that the compounds of formula VIII are substantially inert to the reaction, such as toluene. heat treatment in the presence of xylene or ethyl acetate; the reaction temperature is typically 60-150 ° C. The reaction is usually carried out under a nitrogen atmosphere. in the presence of a radical scavenger (e.g., hydroquinone).

The compounds of formula (VIII) may be cyclized immediately after formation, i.e. without isolation. Compounds of formula VIII may generally be prepared by reaction of compounds of formula XII and XIII wherein R ² and R ⁴ -R ¹³ are as defined above. Preferably, the compound of formula (XIII) is phospholene or a functionally equivalent compound.

The reaction of compounds of formula (XII) and (XIII) is usually carried out in an organic solvent such as toluene. xylene. ethyl acetate. chloroform, dichloromethane. The reaction is usually carried out at elevated temperature, for example 60-150 ° C.

Compounds of formula (XII) may be prepared by a variety of methods known in the art. For example, compounds of formula (XII) may be prepared by reacting compounds of formula (XIV) wherein R ^{2 is} . R ⁴ -R ⁶ and R ^B -R ⁸ are acylated with the compounds of formula XV above wherein R is as defined above.

Compounds of formula (XIV) may be prepared in this manner. reacting a compound of formula VII with a compound of formula XVI wherein R ² and R ¹⁰ are as defined above. Compounds of formula XVI are known. Compounds of formula XVI may be reacted with compounds of formula VII under known acylation conditions.

A (VII). Compounds of formulas XII and XIV are new. Our protection claims extend to these compounds and their preparation.

As stated above, the compounds of formula I and their pharmaceutically acceptable salts and in vivo hydrolysable esters possess antibacterial activity. These compounds are Gram-negative and Gram-positive for in vitro laboratory activity against pathogenic bacteria. proved to be effective against a wide variety of microorganisms. The carbapenem derivatives of the present invention have been found to be sufficiently stable against β-lactamases and have a particularly favorable elimination half-life in mammals. In general, the new compounds were found to be significantly more beneficial than imipenem.

Antibacterial activity of the carbapenem compounds of the present invention can also be demonstrated in vivo by standard screening assays.

Carbapenem compounds are generally only slightly toxic to warm-blooded people. This general finding also applies to the compounds of the invention No toxic symptoms or side effects attributable to the test compound were observed in animals when administered at doses higher than the protective dose against bacterial infection in mice.

The in vitro antibacterial activity data of each of the compounds of Formula I are given in Table I below. The antibacterial activity of the compounds against the microorganisms listed in Table I was measured and the minimum inhibitory concentration (MGK, pg / ml) determined by the agar dilution method using 110 ^J CFU / spot inoculum was used.

/. spreadsheet

MGK. uc / ml

Microorganisms; _us ! Example 1 - Example 2 - Example 4 - Example 10 - Ceftrida da da da axon

Enterobacter cloacae 029 0:06 - 0:03 0:03 0.01 0:06 Enterobacter cloacae I0S 1:00 1.00 0:50 0:25 32 E. coli TEM 0.03 0:02 0.02 0.01 0:03 S. aureus 147N 0:25 0:50 0:25 0.13

The invention is further illustrated by the following non-limiting Examples. Unless otherwise stated in the Examples, (i) NMR spectra were recorded at 200 MHz or 400 MHz, chemical shift values are expressed in ppm on an δ scale;

(ii) in NMR spectra of a mixture of hexadeutero-dimethylsulfoxide (DMSO-d ₆ ) and tetradeuteroacetic acid (CD 3 COOD), the position of the peaks varies with the ratio of the solvent components to each other;

(iii) "allyloxy" means propen-1-yloxy (-OCH 1 CH = CH ₂ );

(iv) Meldrum acid means 2,2-dimethyl-1,3-dioxane-4,6-dione;

(v) evaporation of the solvents under reduced pressure;

EN 211 840 A9 (vi) Abbreviations used for beam spectra have the following meanings: El: electron collision; Cl: chemical ionization; FAB; fast atom bombardment.

Example 1 (IR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-5-hydroxyphenylcarbanoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) - Preparation of disodium salt of methylcarbapenyl-3-carboxylic acid

500 mg (0.72 mmol) of (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3- (allyloxy) -5- / allyl) oxycarbonyl (phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester;

To a solution of 829 mg (5.75 mmol) of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum acid) in a mixture of 8 ml of dimethylformamide and 4 ml of tetrahydrofuran under argon was added 83 mg (0.072 mmol) of teirakis. (triphenylphosphine) palladium is added. The solution was stirred for 2 hours under argon and protected from light. The solution was then diluted with diethyl ether (40 mL), the precipitate was collected by centrifugation and the supernatant removed. The product was washed with resuspension in diethyl ether, separated by centrifugation and dried under very low pressure. The crude product was dissolved in water (10 mL) and the pH was adjusted to 6.8 with sodium bicarbonate. The mixture was filtered and the solution chromatographed on Diaion CHP20P. The appropriate fraction was combined and the product isolated. The title compound was obtained in 66% yield. NMR _(DMSO-d6 + CDjCOOD) 1.18 id. 6H). 1.82 (m. Partially cloudy, 1H), 2.79 (m.

IH). 3.03 (dd. 1H). 3.22 (dd. 1H). 3.38 (quintet.

1H). 3.57 (dd. 1H). 3.82 (quintet, 1H). 3.99 (quintet 1H). 4.19 (dd + m. 2H). 7.13 (I. 1H). 7.65 (t. 1H).

The starting materials are prepared as follows:

Preparation of 3-Allyl-cis-) -5-aminobenzoic acid allyl ester

To a solution of 3-hydroxy-5-nitrobenzoic acid (3.9 g, 21.3 mmol) in dimethylformamide (55 mL) was added anhydrous potassium carbonate (11.78 g, 76.5 mmol). Allyl bromide (5.4 mL, 62.4 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated, water was added to the residue and the pH of the aqueous mixture was adjusted to 5.5. and extracting the product with ethyl acetate. The extracts were combined with aqueous sodium dihydrogen phosphate solution. water, followed by brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated. The residue was chromatographed on silica gel. the eluent was 10: 1 gasoline / ethyl acetate. 5.94 g (90%) of allyl 3- (allyloxy) -5-nitrobenzoic acid are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 4.66 (dt. 2H). 4.87 (dt.

2 H). 5.31-5.52 (m, 4H), 5.94-6.14 (m, 2H), 7.92 (m, 2H). 8.46 (1, 1H);

Mass spectrum (CI): 264 (MH ⁺ )

To a suspension of tin (II) chloride dihydrate (13.7 g, 61 mmol) in ethyl acetate (35 ml) was added a solution of the ester (2 g, 7.6 mmol) in ethyl acetate (15 ml) under reflux under argon. The reaction mixture was refluxed for 4 hours, then cooled and poured into a mixture of 20 mL of aqueous ammonia (d = 0.880) and 20 mL of water. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic solutions were combined, washed with dilute aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. There was obtained 1.53 g (86%) of allyl 3- (allyloxy) -5-aminobenzoic acid as a yellow oil. Nuclear Magnetic Resonance Spectrum (CDCl 3): 3.60 (broad, 2H), 4.53 (dt, 2H), 4.78 (dt, 2H), 5.25-5.44 (m, 4H), 5.966.12 ( m, 2H), 6.43 (dt, 1H), 7.00 (m, 2H); Mass spectrum (CI): 233 (MH) ^& lt ^{; + &gt;.}

Formation of the pyrrolidin-4-ylthioacetate side chain

A suspension of 5.6 g (15 mmol) of 4- (acetylthio) -1- (allyloxycarbonyl) -2-carboxypyrrolidine-cyclohexylamine salt in ethyl acetate was added with 20 mL, followed by 10 mL of 2 N aqueous hydrochloric acid, water, and aqueous sodium chloride, and the ethyl acetate solution was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was evaporated. The corresponding free acid is then obtained. To a mixture of dimethylformamide (0.51 mL, 6.6 mmol) and dichloromethane (20 mL) was added a mixture of oxalyl chloride (0.52 mL, 6 mmol) and dichloromethane (5 mL), and the mixture was heated for 30 minutes under argon. To the Vilsmeier reagent thus prepared, a solution of 1.64 g (6 mmol) of 4 (acetylthio) -1- (a] -yloxycarbonyl)) - 2-carboxypyrrolidine in 7 ml of dichloromethane was added in one portion, and A mixture of N-methylmorpholine (0.79 mL, 7.2 mmol) and dichloromethane (3 mL) was added and the reaction mixture was stirred at -10 ° C for 30 min. The reaction mixture was cooled to -20 ° C and 1.39 g (5.9 mmol) of allyl 3- (allyloxy) -5-aminobenzoic acid and 0.79 ml (7.2 mmol) of N-methylmorpholine were added. A solution of 15 ml of dichloromethane was added dropwise. The mixture was allowed to warm to 0 ° C and allowed to stand for 18 hours. The mixture was diluted with dichloromethane (100 mL), washed with 2N aqueous hydrochloric acid, water, then saturated aqueous sodium bicarbonate. dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The crude product obtained is chromatographed on medium pressure silica gel, eluting with a gradient gradient of petrol / dichloromethane (3: 1 to 2: 1). 2.37 g (81%) of (2S, 4S) -1- (allyloxycarbonyl) -2- (3- (allyloxy) -5-allyloxycarbonate / phenylcarbamoyl) as a gum pyrrolidin-4-yl thioacetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.32 (s, 3H). 2.58 (broad, 2H), 3.39 (dd, 1H), 3.03 (quintet, 1H). 4.13 (dd, 1H), 4.55 (t, partially cloudy, 1H). 4.58 (dt.

2 H). 4.68 (dt, 2H), 4.81 (dt, 2H), 5.23-5.49 (m.

6H), 5.84-6.15 (m, 3H), 7.36 (t, 1H). 7.57 (t. 1H).

7.66 (t, 1H), 9.10 (broad, 1H);

Mass Spectrum (+ FAB): 489 (MH) ⁺ , 511 (M + Na) ⁺

HU 211 840 A9

Formation of pyridin-4-yl thiols

1.89 g (3.9 mmol) of (2S, 4S) -4- (acetylthio) -1 (allyloxycarbonyl) -2- (3- (allyloxy) -5- (allyloxycarbonyl) - phenylcarbamoyl) -pyrrolidine is dissolved in 25 ml of allyl alcohol and argon gas is bubbled in the solution. To the mixture was added 1N aqueous sodium hydroxide solution (4 mL, 4 mmol), the reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue is taken up in 100 ml of ethyl acetate, the solution is washed with 2N aqueous hydrochloric acid, water, aqueous sodium hydrogencarbonate solution, and finally aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. 1.57 g (76%) of crude (2S, 4S) -1- (allyloxycarbonyl) -2- (3-allyloxy / -5- / allyloxycarbonyl / phenylcarbamoyl) as a gum. Pyrrolidin-4-yl-thiol is obtained. This crude product was used directly in the next reaction.

Preparation of protected carbapenem chemicals

1.5 g (3 mmol) of allyl (1R, 5R, 6S, 8R) -6- (1-hydroxy-ethyl) -1-methyl-2- (diphenyl-phosphoryloxy) -carbapenem-3-carboxylic acid under argon Dissolve in 18 ml of anhydrous acetonitrile and cool to -20 ° C. and 0.63 mL (3.6 mmol) of diisopropylethylamine was added. Thereafter, 1.57 g (3.5 mmol) of (2S, 4S-11,10-allyloxycarbonyl) -2- (3- (allyloxy) -5- (allyloxycarbonyl) phenylcarbamoyl) were added. A solution of pyrrolidin-4-yl-thiol in 12 ml of acetonitrile is added dropwise. The reaction mixture was kept at -20 ° C for 3 days. The solvent was evaporated and the residue was purified by medium pressure chromatography on silica gel. Elution 40:60 and

Between 70:30 gradient gradient dichloromethane / ethyl acetate mixtures were used. 1.25 g (60%) of (1R, 5S, 6S, 8R.2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxy) -5- (allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

NMR (CDC1 _3): 1.23 (d, 3H), 1.35 (d,

3H), 2.65 (broad, 2H), 3.26, 3.31 (overlapping dd and m.

2 H). 3.46 (m. 1H), 3.79 (quintet, 1H), 4.01 (dd.

1H), 4.19-4.29 (m, 2H), 4.50-4.78 (m, 9H), 5.195.46 (m, 8H). 5.83-6.12 (m, 4H), 7.36 (broad s.

1H), 7.64 (m. 2H). 9.00 (broad, 1H): Mass Spectrum (+ FAB): 696 (MH) ⁺ , 718 (M + Na) ⁺

The allyl (1R, 5S, 6S, 8R) -6- (1-hydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid is prepared as follows:

2.66 mmol (1R, 5S, 6S, 8R) -6- (1-Hydroxyethyl) -1-methyl-2-oxo-carbapenam-3-carboxylic acid allyl ester (2-diaΖΟ-3-ΟΧΟ-4- The compound formed directly by reaction of 1-4- (3- (1-hydroxy-elyl) -2-oxo-azetidin-4-yl) -butyric acid ester with rhodium octanoate: see, for example, European Patent Application 208,889. ) and a solution of 1.1 equivalents of diisopropylethylamine in acetonitrile are added dropwise at 0 DEG C., 1.1 equivalents of diphenylchlorophosphate under argon. The solution was stirred for 30 minutes at room temperature. The desired 2- (diphenylphosphoryloxy) carbapenem compound is formed.

Similarly, the preparation of II. Compounds of formula XVII listed in Table II. Compounds of formula tXVII

The substituent on the phenyl ring is a

The number of the example 2 3 4 5 6 R ¹ R2 positions -> ^H COOH cl H H Me H 3 H ^H COOH H H cl Me H 4th H COOH H H H Me ^H 5th H COOH H H SO _: CH, Me ⁶ H COOH F H H Me H 7th H COOH H H F Me H 8th F COOH F H H Me H 9th H COOH COOH H H Me H 10th H COOH CH H ^H Me ^H 11th H COOH H COOH H Me H 12th H COOH H H H Me H 13th H COOH H CON, H Me H 14th H COOH H H CON Me H 15th CONMe ₂ COOH H H H Me H 16th II COOH H NHCOCHj H Me H 17th H COOH NHCOCH, H H Me H 18th H COOH H NHSOiMe H Me H

HU 211 840 A9

The substituent on the phenyl ring is a The number of the example 2 3 4 5 6 R ¹ R2 positions 19th H COOH H SO ₃ H H Me H 20th H COOH H H H H H 21st H COOH H CN H Me H 22nd - H COOH H OMe H Me H 23rd H COOH H H SOMe Me H 24th H COOH H SO ₂ Me H Me H 25th H COOH H CF ₃ H Me H 26th H COOH H H OMe Me ^H 27th H COOH OMe H H Me H 28th OMe COOH H H H Me H 29th H COOH H H Me Me H 30th H COOH Me H H Me H 31st H COOH H Me H Me H 32nd H COOH H COOMe H Me H 33rd H COOH F H F Me H 34th H COOH OMe H OMe Me H 35th H COOH H H CN Me H 36th H COOH H F H Me H 37th ^H COOH H H H Me Me

Me = methyl group

Example 2

UR5S, 6S.8R, 2'S.4'S) -2- (2- [3-Carboxy-4-chloro-phenylcarbanoyl] -pyrimidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl Preparation of -carbapenem-3-carboxylic acid di-sodium salt 35

This compound was prepared according to the procedure of Example 1. except that after the addition of palladium catalyst, the solution is heated slightly to dissolve the catalyst and then for 1 hour under argon. stir lightly. To the mixture was added a solution of the sodium salt of 2-ethylhexanecarboxylic acid in tetrahydrofuran, and the resulting mixture was poured into tetrahydrofuran with vigorous stirring. The precipitate was collected by centrifugation and the supernatant was removed. The product was resuspended in tetrahydrofuran and washed twice by centrifugation and then dried under very low pressure. The title compound is obtained.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.17 (d 6H.). 1.85 (m, cloudy, 1H), 2.73 (m, cloudy).

JH). 2.95 (dd. 1H), 3.21 (dd, 1H), 3.40 (m, 1H),

3.54 (dd, 1H). 3.78 (quintet, 1H), 3.99 (t, JH), 4.11 (t, 1H). 4.18 (dd. 1H), 7.41 (d, 1H), 7.75 (dd, 1H),

8.06 (d, 1H):

Mass Spectrum (+ FAB): 532/534 (MH) ⁺ , (Na salt) ⁺ : 55 554/556 (Na _; salt) ⁺ .

The starting materials were prepared as follows:

2-Chloro-5-nitrobenzoic acid was allylated as described in Example 1, except that toluene was used as the solvent for the final extraction. 2-Chloro-5-nitrobenzoic acid is obtained on allyl ester.

NMR (CDC1 _3):.... 4.89 (dt 2HJ 5335.51 (m.2H), 5.96 to 6.15 (m IH), 7.66 (d, IH), 8.27 ( dd, 1H), 8.72 (d, 1H);

Tom spectrum (Cl): 241/243 (M ⁺ j. 259/261 (M + NH 3).

A mixture of stannous chloride dihydrate and ethanol is refluxed under argon until a solution is formed. The heater is removed and an ethanolic solution of the nitro compound obtained above is added to the side. The reaction mixture was refluxed for 3 hours, cooled and the solvent evaporated. The residue was dissolved in ethyl acetate and made basic with aqueous ammonia (d = 0.880). The organic tin salts are decanted from the precipitated tin salts and the suspension is re-extracted as above. The organic phases were combined, washed with dilute aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The allyl 5-amino-2-chlorobenzoic acid is obtained. NMR (CDC1 _3): 3.74 (br, 2H), 4.81 (dt, H), 5.27 to 5.47 (m, 2H) ', 5.93 to 6.13 (m, IH ), 6.73 (dd, 1H), 7.15 (d, 1H), 7.24 (d, 1H); Mass spectrum (CI): 212/214 (M ⁺ ). 229/231 (M + NH ₄ ) ⁺ .

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography eluting with a gradient from 100: 0 to 60: 95: 5.

I

84 U A9 dichloromethane / diethyl ether mixtures were used. (2S, 4S) 1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-4-chlorophenylcarbamoylpyrrolidin-4-ylthioacetate). CDCl 3): 2.33 (s, 3H), 2.57 (s, 2H), 3.39 (dd. 1H), 4.03 (quintet, 1H), 4.13 (dd. 1H), 4, 55 (t, 1H), 4.66 (dt, 2H), 4.83 (dt, 2H),

5.24-5.47 (m, 4H), 5.85-6.02 (m, 2H), 7.36 (d.

1H), 7.70 idd, 1H), 7.92 (d. 1H), 9.32 (broad, 1H); Mass Spectrum (+ FAB): 467/469 (MH) ⁺ . 489/491 (M + Naf.

The thioacetate compound thus obtained is deacetylated as described in Example 1 and then the resulting thiol is condensed with carbapenem phosphate as described in Example 1. Its products are purified by chromatography, eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -211- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -4-chlorophenylcarbamoyl) pyrrolidine-4 allyl thio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDC13) 1.24 (d. 3H), 1.36 (d.

3H). 2.65 (broad 2H). 3.25 (overlapping 'dd and m. 2H),

3.48 (m. 1H). 3.80 (quintet 1H). 3.98 (dd. 1H).

4.20-4.31 (overlapping quintet. 2H). 4.52 (l. 1H). 4.514.76 (m. 4H). 4.83 (dt. 2H), 5.20-5.47 µm. 6H);

5.85-6.11 (m. 3H). 7.39 (d. 1H). 7.77 (dd. 1HI.7.99

Id. 9.05 (broad IH):

Mass Spec (+ FABi: 674/676 (MHC. 696/698) + NaC.

Example 3 (IR. 5S. 65.8R. 2'S, 4'S) -2- [2- (5-Carboxy-2-chloro-phenylcarbanoyl] -pyrrolidin-4-yl-thio) -6-H-hydroxy ethyl) -Ninylcarbapenem-3-carboxylic acid disodium salt

This compound was prepared as described in Example 2 from the appropriate starting material.

NMR _(DMSO-d6 + CD, COOD): 1.16 (d, 3H.). 1.19 (d. 3H). 1.82 (m. Cloudy. 1H). 2.70 (dd overlapping and m. 2H). 3.22 (dd. 1H), 3.35-3.60 (overlapping m. 3H). 3.95 ^, 08 (overlapping m. 2H), 4.16 (dd.

IH). 7.57 (d. 1H). 7.69 (dd. 1H). 8.36 (d. 1H); Mass Spectrum (+ FAB); 532/534 (MH) ⁺ . (Na salt) ⁺ ;

554/556 (Na ₂ salt) ⁺ .

The starting materials were prepared as follows:

4-Chloro-3-microbenzoic acid was allylated as described in Example 1. Allyl 4-chloro-3-nitrobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 4.86 (d, 2H), 5.31 -

5.48 (m, 2H), 5.94-6.13 (m, 1H). 7.50 (d. 1H), 8.18 (dd, 1H), 8.52 (d, 1H):

Mass spectrum (CI): 241/243 (M ⁺ ), 259/261 (M + NH 3) ⁺ .

The nitro compound thus obtained was reduced as described in Example 2 to give the allyl 3-amino-4-chlorobenzoic acid.

Nuclear Magnetic Resonance Spectrum (CDC13): 4.08 (broad, 2H), 4.79 (dt, 2H). 5.25-5.44 (m. 2H). 5.92-6.11 (m. 1H).

7.30 (d. 1H). 7.38 (dd, 1H), 7.47 (d, 1H);

Mass spectrum (CI): 212/214 (M ⁺ ), 229/231 (M + NH 3) ⁺ .

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography eluting with a gradient of dichloromethane / diethyl ether (100: 95 to 5: 5). (2S, 4S) 1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2-chlorophenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 2.32 (s, 3H). 2.56 (broad 1H), 2.66 (broad 1H), 3.43 (dd, 1H), 4.04 (quintet, 1H), 4.16 (dd, 1H), 4.61 (t, 1H), 4.66 ( dt.

2H), 4.82 (dl. 2H), 5.21-5.45 (m, 4H), 5.84-6.11 (m, 2H). 7.45 (d, 1H), 7.77 (dd, 1H), 9.00 (d, 1H).

9.08 (broad 1H);

Mass Spec (+ FAB): 467/469 (MH + 489/491 (M + N

The thioacetate thus obtained was deacetylated as described in Example 1. then condensing the resulting thiol with carbapenem phosphate as described in Example I. The product is purified by chromatography. eluting with a gradient gradient of dichloromethane / ethyl acetate mixtures of pure dichloromethane to pure ethyl acetate (1R, 5S, 6S.8R.2'S.4'S) -2- [1- (Allyloxycarbonyl) -2- (5-Allyloxycarbonyl / -2-chlorophenylcarbamoyl) pyrrolidin4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained. .

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.23 (d, 3H). 1.36 (d.

3H). 2.65 (broad 2H). 3.24 (overlapping dd and m. 2Hi.

3.88 (quintet 1H). 4.08 (m. 1H). 4.19-4.30 (overlapping dd and quintet. 2H), 4.60 (l, 1H). 4.67 (m, 4H). 4.82 (dt. 2H). 5.18-5.45 (m. 6H). 5.82-6.01 (m. 3Hi. 7.44 (dd. 1H). 7.76 (dd. 1H). 9.04 (d. 1ΗI. 8.9 ″ (br. 1H);

Mass Spectrum (+ FAB): 674/676 (MH) ⁺ . 696/698 (M + Na) ⁺ .

Example 4 (1S, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxyphenylcarbanoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) ) - Preparation of the disodium salt of methyl carbapenem-3-carboxylic acid

This compound was prepared as described in Example 2 except that a mixture of dimethylsulfoxide and tetrahydrofuran was used as the medium. NMR _(DMSO-d6 + CDjCOOD): 1.18 (d 6H.). 1.94 (m, cloudy, 1H). 2.85 (m. 1H). 3.10 (dd, 1H). 3.23 (dd. 1H), 3.40 (quintet, 1H). 3.66 (dd. 1H), 3.89 (quintet 1H), 3.99 (t, 1H). 4.21 (dd.

1H), 4.27 (t, 1H), 7.46 (t, 1H), 7.71 (d, 1H). 7.86 (d.

1H), 8.27 (s. 1H);

Mass Spectrum (+ FAB): 498 (MH + (Na-salt) ⁺ ; 520 (Na-salt) ⁺ ).

The starting materials were prepared as follows:

3-Nitrobenzoic acid was allylated as described in Example 1 except that diethyl ether was used as the solvent for the final extraction. Allyl 3-nitrobenzoic acid is obtained.

HU 211 840 A9

Nuclear Magnetic Resonance Spectrum (CDC13): 4.88 (d, 2H), 5.335.49 (m, 2H), 5.96-6.17 (m, 1H), 7.66 (t, 1H), 8.41. (td, 2H), 8.88 (t, 1H).

The nitro compound thus obtained was reduced as described in Example 2, except that methanol was used as the solvent. The allyl ester of 3-aminobenzoic acid is obtained,

Nuclear Magnetic Resonance Spectrum (CDCl3): 3.38 (broad, 2H), 4.79 (dt, 2H), 5.24-5.44 (m, 2H), 5.93-6.09 (m, 1H). , 6.86 (dm. 1H), 7.21 (t, 1H>. 7.37 (t, 1H), 7.45 (dt, 1H).

Preparation of side chain pyrimidine-4-ylthioacetate

2.54 g (9.3 mmol) of (2S, 4S) -4- (acetylthio) -1- (allyloxycarbonyl) -2-carboxypyrrolidine, 1.5 g (8.5 mmol) of 3-aminobenzoic acid allyl- A solution of the ester and 2.72 g (11 mmol) of 2-ethoxy-1- (ethoxycarbonyl) -1,2-dihydroquinoline in 50 ml of toluene was stirred for 18 hours at room temperature. The reaction mixture was diluted with 150 mL of ethyl acetate. The resulting mixture was washed with 2N aqueous hydrochloric acid (3 x 30 mL). water, saturated aqueous sodium bicarbonate solution. and finally washed with an aqueous solution of sodium chloride. dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. 3.7 g (100%) of (2S, 4S) -4- (acetylthio) -1- (allyloxycarbonyl) -2- (3-allyloxycarbonyl / phenylcarbamoyl) pyrrolidine are obtained in the form of a gum. : product sufficiently pure for further reaction.

Nuclear Magnetic Resonance Spectrum (CDCl3: 2.32 (s, 3H), 2.60 (br. 2H), 3.40 (dd, 1H), 4.03 (quintet, 1H), 4.13 (dd, 1H), 4.57 (t, 1H)). 4.66 (dm, 2H) 4.82 (dl, 2H).

5.23-5.46 (m. 4H). 5.86-6.12 (m. 2H). 7.41 (t. 1H).

7.82 (d. 1H). 7.91 (d. 1H). 8.07 (vol. 1H). 9.18 (wide.

IH).

The thioacetate thus obtained was deacetylated as described in Example 1. and condensing the resulting thiol with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with a gradient of dichloromethane / ethyl acetate (1: 0 to 1: 1). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidine-4 - l-thio J-6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum data (CDCl3: 1.24 (d. 3H), 1.36 (d.

3H). 2.64 (broad, 2H), 3.26, 3.28 (overlapping dd and m).

2 H). 3.48 (m. 1H), 3.81 (quintet, 1H), 4.01 (dd,

IH). 4.22-4.32 (m. 2H), 4.54 (t, 1H), 4.62-4.75 (m,

4H). 4.82 (m. 2H), 5.19-5.45 (m, 8H), 5.82-6.10 (m, 4H), 7.41 (d, 1H), 7.81 (d, 1H), 7.92 (dm, 1H).

8.11 (t, 1H). 8.98 (broad, 1H);

Mass Spec (+ FAB): 640 (MH) ⁺ , 662 (M + Na) ⁺ .

Example 5

IR, 5S, 6S.8R, 2'S, 4'S) -2- (2- (3-Carboxy-6- (methanesulfonyl) -phenylcarbanoyl / pyrrolidin-4-yl-thio) -6- (II) ) Preparation of hydroxyethyl) -1-ivethylcarbapenem-3-carboxylic acid disodium salt

This compound was prepared according to the procedure of Example 1 from the corresponding protected carbapenem derivative.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.20 (d, 6H), 1.99 (quintet, IH), 2.75 (m, part turbid, IH), 2.87 (dd, 1H), 3.22 (s, 3H), 3.25 (dd. Some cloudy, 1H), 3.44 (quintet, 1H), 3.62 (dd. 1H), 3.75 (quintet, 1H) ), 4.03 (quintet, 1H). 4.16-4.23 (m, 2H), 7.90 (dd, 1H), 8.17 (d, 1H). 9.00 (d, 1H);

Mass Spectrum (+ FAB): 554 (MH) ⁺ , 576 (Na

598 (Na ₂ salt) ⁺ .

The starting materials were prepared as follows:

4- (Methanesulfonyl) -3-nitrobenzoic acid is allylated as described in Example 1. The crude product was purified by chromatography on silica gel eluting with a gradient gradient of dichloromethane: dielyl ether (1: 0 to 9: 1). 4- (Methanesulfonyl) -3-nitrobenzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl j: 3.45 (s, 3H), 4.90 (dt.

2 H). 5.30-5.49 (m, 2H), 5.96-6.12 (m, 1H). 8.29 (d. 1H), 8.40-8.46 (m, 2H).

This compound was reduced as described in Example 1. except that methanol is used as the solvent. 3-Amino-4- (methanesulfonyl) -benzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl 3: 3.07 (s, 3H). 4.82 (dt.

2 H). 5.05 (broad 2H), 5.29-5.44 (m, 2H, 5.956.11 (m, 1H), 7.46 (m, 2H), 7.81 (d, 1H); Mass Spectrum (+ FAB) 256 (MH) ⁺ , 273 (M + NH 3).

The resulting amine compound is condensed with proline carboxylic acid as described in Example I. Its products are purified by chromatography, eluting with a gradient gradient of dichloromethane / diethyl ether (100: 0 to 90:10). (2S, 4S) 1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2- (melanesulfonyl) phenylcarbamoyl) pyrrolidin-4-ylthioacetate we get.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.31 (s, 3H), 2.41 (m.

1H), 2.80 (m, 1H), 3.11 (s, 3H), 3.51 (dd. 1H).

4.00-4.18 (m, 2H), 4.53 (dd, 1H), 4.65 (2m, 2H),

4.87 (dt, 2H), 5.23-5.47 (m, 4H), 5.83-6.13 (m,

2H), 7.93 (dd, 1H), 8.03 (d. 1H). 9.09 (wide s.

IH);

Mass Spec (+ FAB): 511 (MH) ⁺ , 533 (M + Na) ⁺ .

This lyolacetate was deacetylated as described in Example I and then the thiol obtained was condensed with the carbapenem phosphate as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl) -2- (methanesulfonyl) phenylcarbamoyl Pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13) 1.21 (d, 3H). 1.35 (d.

3H), 2.43 (m, 1H), 2.75 (broad, 1H), 3.08 (s 3H).

3.23 (overlapping dd and m, 2H), 3.55 (dd, 1H), 3.85-4.08 (m, 2H), 4.19-4.28 (m, 2H), 4.53-4.68 (m. 5H).

4.86 (dt, 2H), 5.17-5.47 (m, 6H). 5.79-6.12 (m.

HU 211 840 A9

3H), 7.92 (dd, 1H), 8.00 (d. 1H), 9.16 (broad s, 1H), 10.14 (broad, 1H);

Mass Spectrum (+ FAB): 718 (MH) ⁺ , 740 (M + Na) ⁺ .

Example 6

(1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2 '- (3-Carboxy-4-fluoro-methyl-carbanoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - ] -Methylcarbapenene-3-carboxylic acid 199 mg (0.3 mmol) () R.5S.6S, 8R.2'S.4'S) -2- [1 '(Allyloxycarbonyl) -2' - (3 ' - (Allyloxycarbonyl / -4-fluorophenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester and 259 To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum acid) (1.5 mg, 1.8 mmol) in dimethylformamide (1.5 mL) under argon was added 10 mg (0.009 mmol) of tetrakis (triphenylphosphine) - palladium / 0.1 ml tetrabydrofuran. The solution was stirred for 2 hours under argon and a further mixture of 5 mg (0.0045 mmol) of tetrakis (triphenylphosphine) palladium and 0.1 ml of tetrahydrofuran was added. After stirring for 30 minutes, tetrahydrofuran (3 mL) and diethyl ether (9 mL) were added. The precipitated solid was filtered off. It is washed with 9 ml of diethyl ether and dried under very low pressure. 72 mg (49%) of the title compound are obtained.

NMR _(DMSO-d6 + CDjCOOD): 1.30 ld. 6H). 2.00 (ni. Partially cloudy. IH). 2.91 (m partially cloudy. 1H). 3.13 (dd. 1H). 3.36 (dd, 1H).

3.55 (dq. 1H). .3.73 (dd. 1H). 3.95 lm. IH). 4.12 (ni. 1H). 4.29 (dd. 1H). 4.34 (dd. 1H). 7.40 (dd. 1H).

7.98 (m. 1H). 8.32 (dd. 1H);

Spectrum (+ FAB): 494 (MH) ⁺ . 516 (M + Na) ⁺ .

The starting materials were prepared as follows:

Preparation of 5-Allyl-2-fluorobenzoate, allyl ester

To a solution of 2-fluoro-5-nitrobenzoic acid (4.16 g, 22.5 mmol) in dimethylformamide (mL) was added anhydrous potassium carbonate (4.65 g, 33.7 mmol). The resulting mixture was stirred at room temperature for 18 hours and then poured into 450 ml of water. The aqueous mixture was extracted with diethyl ether (3 x 100 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The resulting 5.4 g of a yellow oily residue is purified by chromatography on silica gel using ethyl acetate / hexane (12.5: 87.5, v / v) as the eluent. 4.64 g (92%) of 2-fluoro-5-nitrobenzoic acid allyl ester are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 4.89 (d, 2H). 5.30 5.50 (m, 2H), 5.90-6.10 (m, 1H). 7.32 (t, 1H). 8.38-8.46 (m, 1H). 8.86 (dd, 1H);

Mass Spec (EI): 226 (MH ⁺ ). (Cl): 225 (M) ⁺ , 243 (M + NH ₄ ) ⁺ .

2.47 g (10.97 mmol). a solution of the above ester in ml methanol with stirring,

A solution of tin (II) chloride dihydrate (9.89 g, 43.76 mmol) in concentrated hydrochloric acid (9 mL) was added at 5-15C. The reaction mixture was stirred overnight at room temperature and then poured into water (200 mL). The aqueous mixture

Neutralize with 17.6 g of solid sodium bicarbonate to pH 6. The mixture was extracted with chloroform (3 x 200 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. 2.09 g (98%) of the allyl 5-amino-2-fluorobenzoic acid are obtained as a yellow oil. Nuclear Magnetic Resonance Spectrum (CDCl3): 3.60 (bs, 2H).

4.82 (dt, 2H), 5.25-5.48 (m, 2H), 5.93-6.12 (m.

1H), 6.78 (ddd, 1H), 6.93 (dd, 1H), 7.20 (dd. 1H); Nuclear Magnetic Resonance Spectrum (EI): 195 µM (Cl): 196 (MH) ⁺ , 213 (M + NH ₄ +).

The resulting amine was condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on silica gel eluting with ethyl acetate / hexane (42.5: 57.5, v / v). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -4-fluorophenylcarbamoyl) pyrrolidin4-ylthioacetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.32 (s, 3H). 2.502.70 (bs, 2H), 3.40 (d, 1H). 3.98-4.20 (m.

2 H). 4.56 (1H. 1H), 4.67 (dt, 2H). 4.84 (dt. 2Hl.

5.20-5.50 (m. 4H), 5.83-6.12 (m. 2H), 7.10 (dd.

IH). 7.80-7.89 (m, 1H), 7.93 (dd. 1H). 8.90-9.40 (broad s, 1H);

Mass Spectrum (+ FAB): 451 (MH +, 473 (M + Nap).

Conversion to pyriditol-thiol:

1.33 g (2.96 mmol) of (2S, 4S) -1- (allyloxycarbonyl) 2- (3-allyloxycarbonyl / -4-fluorophenylcarbamoyl) pyrrolidin-4-yl argon gas was bubbled through a solution of thioacetate in allyl alcohol (30 mL). To the solution was added 1N aqueous sodium hydroxide solution (3.1 mL, 3.1 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.3 ml of acetic acid, the mixture was stirred for an additional 5 minutes and then the volatiles were evaporated. The residue was taken up in 60 ml of ethyl acetate. solution with 60 ml of saturated aqueous sodium bicarbonate solution. then washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. 1.07 g (89%) of (2S, 4S) -1- (allyloxycarbonyl) -2- (3-allyloxycarbonyl / -4-fluorophenylcarbamoyl) pyrrolidine-4 were obtained as a gum. -Il-thiol is obtained. The crude products are used directly in the next step.

The thiol thus obtained was condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography on silica gel (eluent: ethyl acetate / dichloromethane 75/25 by volume). () R, 5S, 6S, 8R, 2'S.4'S12- [1- (Allyloxycarbonyl) -2- (3-carboxy-4-fluorophenylcarbamoyl) -pyrrol di η-4-yl -thio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester NMR (CDCl 3) 1.24 (d. 3H) 1.35 (d.

3H), 2.40-2.80 (broad, 2H), 3.24-3.28 (m, 2H).

3.40-3.58 (broad 1H), 3.80 (dq, 1H). 3.99 (dd.

1H), 4.19-4.33 (m, 2H). 4.53 (t, 1H). 4.59-4.77 (m.

4H), 4.77-4.88 (m, 2H), 5.17-5.50 (m, 6Hl, 5.806.13 (ni. 3H), 7.10 (dd. 1H, 7.82-7.95 (m). . IH).

8.00 (dd, 1H), 8.70-9.20 (broad 1H);

HU 211 840 A9

Mass Spectrum + FAB): 658 (MH +).

Example 7 R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [5 -] (Arboxin-2-Fluorophenylcarbamoyl / pyrrolidin-4-ylthio) -6- ! (1 -hydroxyethyl) - - prepared methyl-carbapenem-3-carboxylic acid: This compound was prepared as described in Example 6, but using the appropriate protected carbapenem NMR (DMSO-d ₆ + CD ₃ COOD): 1st , 30 (d, 6H), 1.84 (m. 1H), 2.80-2.93 (m. 2H), 3.36 (dd.

IH). 3.58 (m. 1H), 3.66 (dd, 1H). 3.81 (m, 1H).

4.09 (dq. 1H), 4.21 (m, 1H), 4.31 (dd, 1H). 7.56 (dd, 1H), 8.07 (m, 1H), 8.90 (d. 1H); Mass Spectrum (+ FAB): 494 (MH) ⁺ , 516 (M + Na) ⁺ .

The starting materials were prepared as follows:

Preparation of 3-Alino-4-phenyl (trans-benzoic acid allyl ester)

4-Fluoro-3-nitrobenzoic acid is allylated as described in Example 6. Allyl 4-Fluoro-3-nitrobenzoic acid is obtained.

NMR (CDC1 _3): 4.87 (. Dt 2H), 5.485.32 (m, 2H.), 5.95 to 6.14 (m, IH). 7.40 (dd, 1H).

8.30-8.38 (m. 1H), 8.76 (dd, 1H);

Tom spectrum (EI): 225 (M ⁺ ). (Cl): 225 (M ⁺ ). 243 (M + NH 3 F).

The compound thus obtained was reduced as described in Example 2, except that methanol was used as the solvent. 3-Amino-4-fluorobenzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCL): 3.70 (br, 2H). 4.79 (dt. 2H). 5.25-5.44 (m. 2H). 5.96-6.09 (m. 1H).

7.02 (dd. 1H). 7.41-7.54 (m. 2H);

Tonspectrum (EI): 195 (M ⁺ ). (Cl): 196 (MH) ⁺ .

The resulting amine is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on silica gel eluting with 50:50 ethyl acetate / hexane. (2S, 4S) -1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2-fluorophenylcarbamoyl) -pyrrolidin-4-ylthioacelate is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.33 (s, 3H), 2.62 (s, 2H). 3.40 (dd, 1H), 3.98-4.20 (m, 2H), 4.60 (t 1H). 4.67 (dt, 2H), 4.82 (dt. 2H). 5.2-5.5 (m,

4H). 5.8-6.15 (m. 2H), 7.16 (dd, 1H), 7.83 (ddd.

IH). 8.97 (dd, 1H). 9.27 (broad, 1H); Mass Spec (EI): 451 (MH) ⁺ , (Cl): 451 (MH) ⁺ .

The thioacetate thus obtained is deacetylated to the corresponding thiol. the resulting thiol is condensed with the carbapenem phosphate compound as described in Example 6 and the product is purified by chromatography. Elution was carried out with ethyl acetate. (LR, 5S, 6S, 8R, 2'S, 4'S) -2- [l- (allyloxy carbonyl) -2- (5- / allyloxy carbonyl / -2-fluoro-phenylcarbamoyl) -pyrrolidine 4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained. NMR (DMSO-d ₆ + CD ₃ COOD): 1.90 (.. Ni partly cloudy IH). 2.78 (m, 1H), 3.22 (dd.

1H), 3.26 (m. 1H), 3.52 (m, 1H), 3.83-4.03 (m,

2H), 4.09 (dd. 1H). 4.22 (m, 1H), 4.53 (m, 1H),

4.53-4.65 (m. 4H). 4.80 (dt, 2H). 5.05-5.43 (m,

6H), 5.73-5.98 (m, 2H), 5.98-6.09 (m. 1H), 7.38 (dd. 1H), 7.78 (broad s, 1H), 8.49 ( m, 1H), 8.62 (d,

H)

Tom spectrum (+ FAB): 658 (MH) ⁺ , 680 (M + Na) ⁺ .

Example 8 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-2,4-difluorophenylcarbamoyl] -pyrrolidin-4-yl) -6- (1-hydroxyethyl) Preparation of N-methylcarbapenem-3-carboxylic acid This compound was prepared as described in Example 7 from the corresponding protected carbapenem compound. NMR Spectrum: (DMSOd _b + CD ₃ COOD): 1.29 (d, 6H). 1.94-1.99 (m, partially distorted, 1H). 2.813.07 (m, 1H), 3.05 (dd, 1H), 3.37 (dd, 1H), 3.56 (m,

IH). 3.75 (dd, 1H). 3.92 (q, 1H), 4.10 (dq. 1H).

4.29-4.38 (m. 2H), 7.22 (t, 1H), 8.07 (m, 1H); Mass Spec (+ FAB): 512 (MH) ⁺ , 534 (M + Na) ⁺

The starting materials were prepared as follows:

Preparation of allyl 3-amino-2,6-difluorobenzoic acid

2,6-Difluoro-3-nitrobenzoic acid was allylated as described in Example 6. 2,6-Difluoro-3-methyl-benzoic allyl ester is obtained.

NMR (CDC1 _3): 4.90 (. Dt 2H). 5.335.50 (m, 2H). 5.95-6.03 (m, 1H). 7.09-7.27 (ddd.

IH). 8.22-8.27 (ddd. 1H);

TMS (EI): 244 (MH) ^&lt; ^{+ &gt};. (Cl): 261 (M + NH ₄ ) ⁺ .

This ester was reduced as described in Example 2. except that methanol is used as the solvent. Allyl 3-amino-2,6-difluorobenzoic acid is obtained.

NMR (CDC1 _3): 4.86 (. Dt 2H). 5.275.49 (m. 2H). 5.95-6.09 (m. 1H). 6.77-6.86 lm.

2 H);

Mass Spectrum (EI): 213 (M ⁺ ). (Cl): 214 (MH: *

The resulting amine is cindered with proline carboxylic acid as described in Example 1. The product was purified by chromatography, eluting with 40:60 ethyl acetate / hexane.

(2S, 4S) -1- (Allyloxycarbonyl) -2- (2-allyloxycarbonyl-2,4-difluorophenylcarbamoyl) -pyrrolidin-4-ylthioacetate.

NMR (CDC1 _3): 2.32 (s, 3H). 2.60 (broad, 2H), 3.40 (dd, 1H), 3.95-4.19 (m, 2H), 4.57 (t 1H), 4.67 (dt, 2H), 4.86 (dt, 2H) ), 5.20-5.50 (ni.

4H), 5.81-6.13 (m, 2H), 6.95 (ddd. 1H), 8.4 (ddd.

1H), 9.2 (broad, 1H);

Mass Spectrum (+ FAB): 469 (MH) ⁺ .

The thioacetate thus obtained is deacetylated to the corresponding thiol and then the thiol is condensed with the carbapenem phosphate compound as described in Example 6. The product was purified by chromatography on silica gel using ethyl acetate as the eluent. (IR, 5S, 6S, 8R, 2'S, 4'S) -2- [l- (allyloxy carbonyl) -2- (3-carboxy-2,4-difluoro-phenylcarbamoyl) pyrrolidin-4-ylthio ] This gives 6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

HU 211 840 A9

NMR (CDC1 _3): 1.26 (d, 3H). 1.36 (d,

3H). 1.80 (d, 1H). 2.62 (broad, 2H), 3.19-3.36 (m,

2 H). 3.44 (dd. 1H), 3.08 (q, 1H), 4.05 (dd. 1H),

4.19-4.33 (m, 2H), 4.50-4.80 (m, 5H). 4.86 (dt.

2H |. 5.17-5.50 (m, 6H), 5.82-6.10 (m, 3H), 6.95 (dt, 1H). 8.38 (dt, 1H), 9.00 (broad, 1H); Tom spectrum (+ FAB): 676 (MH) ⁺ , 698 (M + Na) ⁺ .

Example 9 (1R, 5S, 6S, 8R, 2'S, 4'S, 1-2-12- (3,4-Dicarboxy-phenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxy) ethyl) -1-ethylcarbapenene-3-carboxylic acid trisodium salt

This compound was prepared as described in Example 2. except that a mixture of dimethylsulfoxide and tetrahydrofuran is used as the medium. NMR (DMSO-d ₆ + CD ₃ COOD): 1.18 (d 6H.). 1.84 (m. Partially distorted. IH). 2.78 (m. 1H).

3.02 (dd. 1H). 3.23 (dd. 1H). 3.40 (quintet 1H).

3.58 (dd. 1H), 3.83 (quintet 1H). 4.00 (quintet.

IH). 4.20 (overlapping dd and m. 2H). 7.92 (dd. 1H). 8.17 (d. 1H). 8.33 (d, 1H):

Mass Spectrum (+ FAB): 542 (MH) ⁺ . (Na salt) ⁺ . 564 (Na ₂ salt) ⁺ .

The starting material was prepared as follows:

2-Carboxy-4-nitrobenzoic acid was allylated as described in Example 1. 2- (Allyloxycarbonyl) -4-nylrobenzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 4.85 (dt. 4H), 5.295.47 (m.p. 4H). 5.91-6.12 (m. 2H). 7.88 (d. 1H). 8.38 (dd. 1H). 8.63 (d. 1H).

The nitro compound thus obtained was reduced as described in Example 2. The product was purified by medium pressure chromatography on silica gel using dichloromethane / diethyl ether gradient gradient from 100: 0 to 90:10 as the eluent. 2- (Allyloxycarbonyl) -4-aminobenzoated allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 3.94 (broad, 2H).

4.71-4.80 (m. 4H). 5.22-5.42 (m, 4H). 5.88-6.10 (ni. 2H). 6.69 (dd. 1H), 6.75 (d. 1H). 7.74 (d, 1H).

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by medium pressure chromatography on silica gel eluting with dichloromethane, gradually increasing the diethyl ether content to 20 volumes. (2S, 4S) -1- (Allyloxycarbonyl) -2- (3,4- (di-allyloxycarbonyl) -phenylcarbamoyl) -pyrrolidin-4-ylthioacetal.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.32 (s, 3H), 2.59 (broad, 2H), 3.37 (dd, 1H). 4.03 (quintet, 1H). 4.12 (dd. 1H). 4.56 (t, 1H), 4.67 (d, 2H), 4.77 (t, 4H),

5.25-5.42 (ni. 6H). 5.84-6.11 (m. 3H); 7.79 (m.

3H). 9.52 (broad, 1H).

The resulting thioacetate is converted to the corresponding thiol by deacetylation and the resulting thiol is then condensed with the carbapenemphosphal compound as described in Example 1 without further purification. The resulting product was purified by medium pressure chromatography on silica gel eluting with dichloromethane: ethyl acetate (3: 2). (LR, 5S, 6S, 8R, 2'S, 4'S) -2- [l- (Allyl-benzyloxycarbonylamino) -2- (3,4 / di-allyl-oxycarbonyl / phenylcarbamoyl) -pyrrolidine 4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.24 (d, 3H), 1.35 (d.

3H), 2.62 (broad, 2H). 3.26 (overlapping dd and m. 2H).

3.47 (broad, 1H). 3.81 (quintet, 1H), 3.97 (dd, 1i).

4.19-4.29 (overlapping m, 2H), 4.53 (t, 1H), 4.62-4.82 (m, 8H), 5.19-5.44 (m, 8H), 5.84-6.07 (m. 4H).

7.82 (s, 3H), 9.30 (broad, 1H).

Example 10 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-4-hydroxyphenylcarbamoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) ) - Preparation of -methyl-carbapenem-3-carboxylic acid This compound was prepared as described in Example 1 from the corresponding protected derivative except that. that the resulting crude acid, being sufficiently pure, is not chromatographed.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.17 (d 6H.). 1.95 (ni, distorted, 1H), 2.87 (m, distorted, 1H).

3.17 (dd. 1H), 3.25 (dd. 1H), 3.42 (dt. 1H). 3.75 (dd, 1H). 3.99-4.05 <m. 2 H). 4.22 (dd, 1H). 4.33 tt.

IH). 6.76 (d. 1H). 7.56 (dd. 1H). 7.97 (d 1H): Mass Spectrum (+ FAB): 492 (MH) ⁺ , 514 (M + Naf).

The starting materials are prepared as follows:

2-Hydroxy-5-yl-nitrobenzoic acid was allylated as described in Example 1. with the exception that diethyl ether is used as the solvent for the last extraction. Allyl 2- (allyloxy) -5-nitrobenzoic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.82 (m, 4H). 5.265.55 (m. 4H). 5.97-6.13 (τη. 2H). 7.49 (d, 1H). 8.41 (dd, 1H). 8.52 (d. 1H).

The nitro compound thus obtained was reduced as described in Example 2 except that methanol was used as the solvent and basified with sodium bicarbonate solution. The allyl 2- (allyloxy) -5-aminobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 3.23 (broad, 2H). 4.53 (dt, 2H), 4.79 (d, 2H), 5.21-5.49 (m. 4H). 5.936.14 (m. 2H). 6.80 (m. 2H), 7.16 (d, 1H).

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (100: 0 to 85:15). (2S, 4S) -1- (Allyloxycarbonyl) -2- (4- (allyloxy) -3-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.33 (s, 3H). 2.56 (br. 2H), 3.39 (dd. 1H), 4.01 (quintet, 1H). 4.13 (dd, 1H). 4.52 (t, 1H). 4.60 (dt, 2H), 4.66 (m. 2H).

4.81 (d. 2H), 5.23-5.51 (m, 6H), 5.85-6.13 (m.

3H), 6.91 (d. 1H). 7.76 (dd. 1H). 7.81 (d. 1H). 8.97 (broad, 1H).

The thioacetate thus obtained is deacetylated to the corresponding thiol. followed by the thiol obtained as described in Example I.

Condensed with the carbapenem phosphate compound according to A9. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (4- (allyloxy) -3- (allyloxycarbonyl) phenylcarbamoyl) Pyrrolidin-4-ylthio] -6 - (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid alpha-ester.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.24 (d, 3H), 1.36 (d,

3H). 2.57 (br, 2H), 3.25, 3.28 (overlapping dd and quintet, 2H), 3.47 (br, 1H), 3.78 (quintet, 1H), 4.01 (dd, 1H) ), 4.18 ^ 1.27 (overlapping dd and m, 2H), 4.51 tt, 1H), 4.58 ^ 4.79 (m, 6H). 4.79 (dt, 2H), 5.19-5.51 (m, 8H), 5.83-6.12 (m, 4H), 6.93 (d, 1H), 7.79 (dd, IH). 7.85 (d, 1H). 8.88 (broad, 1H);

Mass Spectrum (+ FAB): 696 (MH) ⁺ , 718 (M + Na) ⁺ .

Example 1 (1R, 5S, 65.8R, 2'S, 4'S) -2-1,2- [3,5-Dicarboxyphenylcarbamoyl] -pyrimidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl-carbapylene Preparation of -3-carboxylic acid

This compound was prepared as described in Example 1. with the exception that the crude acid, which is sufficiently pure, is not chromatographed. NMR (DMSO-d ₆ + CD ₃ COOD): 1.15 (d 6H.). 1.77 (m, partially distorted, 1H), 2.69 (m, partially distorted, 1H). 2.85 (m. Partially distorted, IH),

3.19 (dd. 1H). 3.33-3.51 (m. 2H). 3.71 (quintet 1H). 3.94 (quintet. 1H) .4.03 (1. 1H). 4.15 (dd. 1H).

8.18 (t. 1H). 8.45 (d, 2H):

Mass Spectrum (+ FAB): 520 (MH) ⁺ , 542 (M + N

The starting materials were prepared as follows:

3-Carboxy-5-nitrobenzoic acid was allylated as described in Example 1. Allyl 3- (allyloxycarbonyl) -5-nitrobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 4.89-4.93 (m, 4H).

5.33-5.50 (m. 4H). 5.97-6.17 (m. 2H), 9.00 (t. 1H),

9.04 (d. 2H).

The nitro compound thus obtained was reduced as described in Example 2. Allyl 3- (allyloxycarbonyl) -5-aminobenzoic acid is obtained.

NMR (CDC1 _3): 3.91 (br, 2H);

4.80-4.84 (m, 4H). 5.26-5.45 (m, 4H), 5.96-6.11 (m. 2H). 7.53 (d, 2H), 8.09 (t, 1H).

The resulting amine compound was condensed with proline carboxylic acid as described in Example 1.

(2S, 4S) -1- (Allyloxycarbonyl) -2- (3,5-di-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained.

NMR (CDC1 _3): 2.33 (s, 3H), 2.60 (br, 2H). 3.40 (dd. 1H), 4.03 (quintet, 1H), 4.14 (dd. 1H). 4.58 (t. 1H), 4.65-4.70 (m, 2H), 4.834.87 (m. 4H). 5.24-5.47 (m. 6H), 5.84-6.16 (m,

3H). 8.39 (d. 2H), 8.45 (t, 1H), 9.36 (broad, 1H).

The resulting lioacetate is converted to the corresponding thiol by deacetylation, which is condensed with the carbapenem phosphate compound as described in Example 1. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3,5-di-allyloxycarbonyl / phenylcarbamoyl) -pyrrolidine-4 allyl] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

NMR (CDC1 _3): 1.23 (d, 3H), 1.35 (d.

3H), 2.63 (broad, 2H), 3.25, 3.29 (overlapping dd and m.

2H), 3.49 (broad, 1H), 3.84 (quintet, 1H), 3.98 (dd,

1H), 4.19-4.30 (m, 2H), 4.55 (t, 1H), 4.63-4.78 (m.

4H), 4.84 (d, 4H), 5.19-5.45 (m, 8H), 5.84-6.12 (m, 4H), 8.46 (s, 3H), 9.18 (broad, 1H); Nuclear Magnetic Resonance Spectrum (+ FAB) 724 (MH) ⁺ , 746 (M + Na) ⁺ .

Example 12 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxyphenylcarbamoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) ) - N -methylcarbapenem-3-carboxylic acid 10 g (12 mmol) of (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (3-Allyloxycarbonyl / phenylcarbamoyl) ) -1- (4-nitrobenzyloxycarbonyl) -pyrrolide η-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ester and To a solution of Meldrum acid (5.2 g, 36 mmol) in tetrahydrofuran (70 mL) was added tetrakis (triphenylphosphine) palladium (1.4 g, 1.2 mmol) under argon, with the exclusion of light. The reaction mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate (230 mL) and added to a solution of sodium bicarbonate (1.5 g) in water (200 mL). To the mixture was added 4 g of 10% palladium on charcoal and the mixture was hydrogenated under a hydrogen atmosphere for 3 hours. The catalyst was filtered off and the filtrate was extracted with ethyl acetate (2 x 100 mL) and diethyl ether (2 x 100 mL). The aqueous phase is concentrated under reduced pressure to a final volume of 250 ml. The solution thus obtained is divided into two portions and each portion is purified by passing through a 1 liter HP20SS column. Water is used as the eluent. The pure product fractions were combined and freeze-dried. 3.5 g of the title compound are obtained in the form of a pale yellow solid.

NMR (DMSO-d ₆ + CD ₃ COOD, the peak positions will vary depending on the exact solvent ratio). 1.19 (d, 6H), 1.94 (. Dt IH), 2.97 (dl 1 H ( 3.13 (dd, 1H), 3.25 (dd, 1H), 3.42 (dt, 1H), 3.68 (dd, 1H), 3.94 (quintet, 1H), 4.02 (quintet, 1H) 4.22 (dd, 1H), 4.32 (t, 1H), 7.46 (t, 1H), 7.73 (dt, 1H), 7.88 (dm, 1H), 8.27 (t, 1H) :

Mass Spectrum (+ FAB): 498 (Na salt), 520 (di-Na salt). The starting material was prepared as follows.

3 g of nitrobenzoic acid (0.3 mol) were allylated as described in Example 1. To a solution of the carboxylic acid in 700 ml of anhydrous dimethylformamide was added 82.7 g (0.6 mol) of solid potassium carbonate with stirring. Slightly exothermic reaction begins. and the mixture thickens. 38.8 ml (0.45 mol) of allyl bromide are added over 30 minutes and the mixture is stirred overnight. The mixture is filtered through diatomaceous earth and the volatiles removed from its hair under reduced pressure. The residue was partitioned between diethyl ether and aqueous sodium bicarbonate. The diethyl ether phase was diluted with dilute aqueous hydrochloric acid.

Wash with aqueous sodium chloride solution and water and dry. then evaporate. 62 g of a yellow oily substance are obtained.

NMR _(DMSO-d6); 4.85-4.92 (m,

2H), 5.27-5.5 (m, 2H), 5.97-6.2 (m, 1H), 7.85 (t.

1H), 8.37-8.42 (dt, 1H). 8.48-8.54 (dq, 1H), 8.64 (vol. 1H).

This oily substance was reduced without further purification with tin (II) chloride as described in Example 6. 53 g of allyl 3-aminobenzoic acid are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 3.6 (broad, 2H), 4.774.82 (dt, 2H), 5.24-5.44 (m, 2H), 5.96-6.1 (m, 1H),

6.83-6.88 (m, 1H), 7.17-7.25 (m, 1H), 7.35-7.47 (m.2H).

26.6 g (0.15 mol) of allyl 3-aminobenzoic acid are suspended in 750 ml of toluene. and in the presence of N- (ethoxycarbonyl) -2-ethoxy-1,2-dihydroquinoline (44.5 g, 0.18 mol), 55.2 g (0.15 mol) of 4- (acetylthio) -1- (4- nitrobenzyloxycarbonyl) -2-carboxypyrrolidine. After stirring overnight, the reaction mixture was diluted with ethyl acetate (2 L) and washed with dilute hydrochloric acid, water and brine. The ethyl acetate layer was dried, evaporated and the residue was recrystallized from ethanol. 67.7 g of (2S, 4S) -4- (acetylthio) -1- (4-nitrobenzyloxycarbonyl) -2- (3- (allyloxycarbonyl) -phenylcarbamoyl) -pyrrolidine are obtained. . NMR _(DMSO-d6): 1.93 (quint.

IH). 2.9 (m. 1Hi. 3.35 (m. 1H). 3.91-4.14 (m, 2H).

4.4y (quintet 1H). 4.81 (dd. 2H). 5.22 (dd. 2H).

5.2-5.44 (m. 2H). 5.95-6.10 (m. 1H). 7.47 (d. 2H).

7.66 (t. 2H). 7.8-7.93 (m, 2H). 8.18-8.3 (m. 2H).

10.31 (s. 1H).

52.7 g (0.1 mol) of the thioacetate thus obtained are dissolved in 1 liter of degassed allyl alcohol and 50 ml of 2N aqueous sodium hydroxide solution are added at 0 ° C. After 3 hours, 52.5 ml of 2N aqueous hydrochloric acid was added. The solvent was evaporated and the residue partitioned between ethyl acetate and aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The resulting thiol is used without further purification in the following reaction.

59.68 g (0.1 mol) of (1R, 5R, 6S, 8R) -6- (1-hydroxyethyl) 1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid 4-nitro- A solution of benzyl ester in 500 ml of acetonitrile and 120 ml of methylene chloride was cooled to -15 ° C and 52.5 ml of ethyl diisopropylamine was added slowly. Thereafter, 0.1 mol of (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (3-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-yl-thiol was added to the mixture under argon atmosphere. of acetonitrile was added and the mixture was allowed to stand overnight. The solvent was evaporated and the residue was chromatographed on silica gel. The eluents were methylene chloride, ethyl acetate and acetonitrile. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (4-Nitrobenzyloxycarbonyl) -2- (3-allyloxycarbonyl) (52.6 g) as a yellow solid -phenylcarbamoyl) -pyrrolidine is obtained, n-4-yl-11-10] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ester. NMR (DMSO-d ₆ + CD ₃ OD): 1.26 (d.

3H), 1.35 (d. 3H), 2.2-2.4 (m, 1H), 2.7-2.95 (m.

1H), 3.28-3.40 (m, 2H), 3.54-3.63 (m, 1H), 3.8 (t.

1H), 4.01-4.1 (q, 1H), 4.21 -4.33 (m, 2H), 4.61 (dd.

1H), 4.73 (d, 2H), 5.17-5.45 (m, 6H), 5.93-6.11 (m, 1H), 7.37-8.22 (complex doublets and doublets doublets. 12H).

Example 13

I JR. 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-carbanyl-phenylcarbamoyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl- thio) -6- (1-hydroxyethyl) -N-methylcarbapenem-3-carbonate

The deprotection and hydrogenation were carried out as described in Example 12 with the difference. 0.44 g of (1R, 5S, 6S, 8R, 2'S.4'S) -2- [2- (3-Allyloxycarbonyl-5-carbamoyl-phenylcarbamoyl) -1- (4-nitrobenzyloxy) carbonyl) pyrrolidin-4-ylthiol-6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ether. After hydrogenation, the aqueous phase was freeze-dried without chromatography on an HP20SS column. 125 mg of the title compound are obtained as a pale yellow solid. NMR (DMSO-d ₆ + CD ₃ COOD): 1.9 (d. 6H), 1.98-2,06 (m IH.), 2.85-2,98 (m IHI..

3.16-3.21 (m. 1H). 3.26 (dd. 1H). 3.43 (quintet.

IH). 3.74 (dd. 1H). 3.91-3.97 (m. 1H). 4.0 (1H).

4.23 (dd. 1H). 4.39 (t. 1H). 8.24 (t. 1H). 8.33 it.

1H), 8.44 (t. 1H).

The starting material was prepared as follows:

By reaction of 5 g of 5-nitroisophthalic acid with one equivalent (2 ml) of allyl bromide, 5-nitroisophalic acid monoallyl ester was prepared as described in Example 1. The organic layer was extracted with aqueous sodium bicarbonate solution. The aqueous phase is separated with 2.7 g of the desired monocarboxylic acid and the organic phase contains 2.7 g of di-allyl ester. 3- (Allyloxycarbonyl) -5-nitrobenzoic acid was obtained as a white solid.

Nuclear Magnetic Resonance Spectrum (CDCL): 4.87 (d, 2H). 5.3-5.3 (q. 2H). 6.15-5.97 (m, 1H), 9.01 (t, 3H); Mass spectrum (CI): 252 (MH &lt; + &gt;).

To a solution of 1.5 g of 3- (allyloxycarbonyl) -5-nitrobenzoic acid and 0.76 g of N-hydroxysuccinimide in 50 ml of methylene chloride is added 1.3 g of dicyclohexylcarbodiimide and the reaction mixture is stirred for 2 hours. stirring at room temperature. The precipitated white solid was filtered off and the filtrate was evaporated to remove volatiles. The resulting activated ester was purified by chromatography on silica gel eluting with methylene chloride. The product was dissolved in methylene chloride for further purification and ammonia gas was introduced at 5 ° C. 1.1 g of 3- (allyloxycarbonyl) -5-nitrobenzamide are obtained in the form of a white precipitate.

NMR _(DMSO-d6): 4.9 (broad d, 2H), 4,884.93 (m, 2H), 6.03-6,11 (m, IH), 7.83 (br s.

1H), 8.55 (br s, 1H), 8.75 (t, 1H). 8.84 (i. 1H).

8.94 (t. 1H);

Mass spectrum (CI): 268 (M + NH ₄ ) ⁺ .

3-Allyloxycarbonyl-5-nitrobenzamide (g) was reduced with tin (II) chloride as described in Example 12.

HU 211 840 A9

0.5 g of 3- (allyloxycarbonyl) -5-aminobenzamidol are obtained.

NMR _(DMSO-d6): 4.78 (. Dt 2H). 5.25.8 (broad, 2H), 5.26-5.45 (m, 2H), 5.91-6.13 (m, 1H), 7.22 (broad s, 1H), 7.27 (t (1H), 7.33 (t, 1H). 7.59 (s, 1H);

Mass Spec (Cl): 221 (MH) ⁺ .

0.75 g of (2S, 4S) -4- (acetylthio) -1- (4-nitrobenzyloxycarbonyl) -2-carboxypyrrolidine are converted to the corresponding acid chloride, and the acid chloride is prepared as described in Example 12, 0.45 g. g of 3- (allyloxycarbonyl) -5-aminobenzamide. The crude product was chromatographed on silica gel eluting with ethyl acetate. 0.58 g of 4- (acetylthio) -1- (4-nitrobenzyloxycarbonyl) -2- (3-allyloxycarbonyl-5-carbamoylphenylcarbamoyl) pyrrolidine is obtained.

NMR _(DMSO-d6): 1.92-2.06 (m, IH). 2.3 (s. 3H), 2.79-2.83 (m, 1H), 3.38 (dd, 1H), 3.97-4.12 (m. 2H). 4.49 (dd, 1H), 4.83 (dt. 2H).

5.19 (dd, 2H). 5.25-5.43 (m, 2H). 5.97-6.11 (m. 1H). 7.31 (bs, 2H). 7.54 (d, 2H). 8.04 (d. 2H), 8.12 (t, 1H). 8.26 (t, 1H). 8.31 (t, 1H). 10.0 (s, 1H). This thioacetate compound was converted to the corresponding thiol as described in Example 12.

0.6 g of (1R, 5R, 6S, 8R) -6- (1-hydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid 4-nitrobenzyl ester ml of acetonitrile as described in Example 12, 0.48 g of (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (3-allyloxycarbonyl / -5- / aminocarbamoyl / -phenylcarbamoyl) -pyrrolidin-4-yl-thiol. The product was purified by flash chromatography. elution was carried out with ethyl acetate followed by ethyl acetate containing 5 volumes of methanol. 0.44 g of (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (4-nitrobenzyloxycarbonyl-2- (3-allyloxycarbonyl) -1- 5-Carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ester is obtained.

NMR _(DMSO-d6): 1.19 to 1.22 (d 6H.). 2.0-2.11 (m. 1H). 2.8-2.92 (m, 1H), 3.32 (dd. 1H),

3.42-3.62 (m. 2H). 3.92-4.2 (m, 2H). 4.31 (broad d, 1H), 4.53 (q, 1H), 4.84 (d, 2H). 4.98-5.46 (m, 6H). 5.98-6.14 (m, 1H), 7.42-8.52 (complex doublets and doublets, 1H).

Example 14 (IR, 5S, 6S.8R, 2'S, 4'S) -2- [2 '- (3-Carboxy-6-carbaloylphenylcarbanoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) ) - Preparation of 1-methylcarbapenem-3-carboxylic acid.

except that (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (3-Allyloxycarbonyl / -6-carbamoylphenylcarbamoyl) -1 - (4-Nylobenzyloxycarbonyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ester. The aqueous phase obtained after hydrogenation is freeze-dried. The title compound is obtained. NMR (DMSO-d ₆ + CD _COOD?): 1,31,38 (2 x d, 6H). 2.0-2.11 (m, 1H), 2.85-2.96 (m, 1H). 3.09 (dd. 1H), 3.37 (dd, 1H), 3.53 (quintet.

1H), 3.79 (dd, 1H), 3.94 (t, 1H), 4.16 (t, 1H). 4.33 (dd, 1H), 4.43 (t, 1H), 7.87 (dd, 1H), 7.97 (d, 1H).

9.12 (d, 1H);

Mass Spectrum (+ FAB): 541 (Na-salt), 563 (di-Na-salt).

The starting material was prepared as follows:

6.33 g of nitroterephthalic acid at -10 'C with 75 ml of methylene chloride and 15 ml of tetrahydrofuran

2.63 ml oxalyl chloride, 2.55 ml dimethylformamide and

7.95 ml of N-methylmorpholine are added. After 1 h, the solvent was evaporated and the resulting mono-acid chloride was dissolved in a mixture of allyl alcohol (20 mL) and tetrahydrofuran (10 mL) without further purification. The solution was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The sodium bicarbonate solution was acidified and extracted with ethyl acetate. 6.8 g of 4- (allyloxycarbonyl) -2-nitrobenzoic acid were isolated from the extract. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.89 (d, 2H). 5.315.49 (m. 2H), 5.95-6.15 (m, 1H), 7.94 (d. 1H). 8.36 (dd, 1H), 8.54 (d, 1H).

This was converted without further purification with the carboxylic acids to the corresponding acid chloride as described above and dissolved in 100 ml of tetrahydrofuran. Ammonia gas was added to the solution at 0 'Con until the reaction was complete. The solution was partitioned between ethyl acetate and water and purified by chromatography on silica gel of the products separated from the organic phase. Elution was carried out with methylene chloride followed by ethyl acetate. The product (4 g), containing a small amount of impurity, was reduced with tin (II) chloride as described in Example 12. 4- (Allyloxycarbonyl) -2-aminobenzamide is obtained.

NMR (DMSO-d _e): 4.79 td. 2 H).

5.22-5.46 (m. 2H). 5.91-6.13 (m. 1H). 7.02 (dd.

IH). 7.37 (d, 1H), 7.61 (d. 1H).

To a suspension of (2S, 4S) -4- (acetylthio) -1- (4-nitrobenzyloxycarbonyl) -2-carboxypyrrolidine (1.58 g) in methylene chloride (25 mL) was added oxalyl chloride (1.52 mL) and a few drops of dimethylformamide are added. After 2 hours, the solvents were evaporated and the resulting acid chloride was dissolved in 10 mL of methylene chloride and dissolved in 0.52 g of 4- (allyloxycarbonyl) -2-aminobenzamide, 10 mL of tetrahydrofuran, 5 mL of methylene chloride and under argon. Add 38 ml of N-methyl morpholine at 0 ° C. The reaction mixture was allowed to stand overnight and then partitioned between methylene chloride and dilute aqueous hydrochloric acid. The methylene chloride layer was washed with water and brine and dried. The product was purified by chromatography on silica gel eluting with increasing volumes of ethyl acetate / methylene chloride. 0.84 g of (2S, 4S) -4- (acetylthio) -1- (4-nitrobenzyloxy) carbonyl) 2- (3-allyloxycarbonyl / -6-carbamoylphenyl) -carban) oil) pyrrolidine is obtained.

Nuclear Magnetic Resonance Spectrum (CDCE) ^: 2.25 (quintet, 1H),

2.29 (s, 3H), 2.83 (m, 1H), 3.53 (dd, 1H), 4.02 (quintet, 1H), 4.2 (dd, 1H), 4.49 (dd, 1H) ), 4.85 (d.

2H), 5.23-5.46 (m, 2H). 5.97-6.13 (m. 1H). 7.3119

HU 211 840 A9

7.5 (broad, 2H). 7.57 (d, 1H). 7.75 (dd. 1H), 7.817.95 (broad, 2H), 9.27 (d, 1H).

This thioacetate compound was converted to the corresponding thiol as described in Example 12.

(1R, 5R, 6S.8R) -6- (1-Hydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) -carbapenem-3-carboxylic acid 4-nitrobenzyl ester was dissolved in 20 mL of acetonitrile. (2S, 4S) -1- (4-Nitrobenzyloxycarbonyl) -2- (2-carbamoyl-5-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidine-4 lithiol. 1.24 g of (1R, 5R, 6S, 8R, 2'S, 4'S) -2- [1- (4-nitrobenzyloxycarbonyl) -2- (3- (allyloxycarbonyl) -6-) are obtained as a yellow foam. Carbamoylphenylcarbamoyl) -pimolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenz-3-carboxylic acid 4-nitrobenzyl ester is obtained.

NMR: 1.23-1.35 (m, 6H). 2.2-2.38 (m, 1H). 2.77-2.93 (m, 1H), 3.27 (dd, 1H). 3.283.42 (m, 1H), 3.65-3.92 (m. 2H). 4.17-4.35 (m, 3H). 4.53 0. 1H), 4.83 (d. 2H). 4.92-5.44 (m, 6H). 5.93-6.11 (m. 1H). 6.22-6.58 (broad, 2H), 7,358.23 Ikomplex, doublets and doublets. JOH)

9.20 amd IH).

Example 15 <IR.5S.6S, 8R.2'S.4'S) -2-12- (2-Dinethylaminocarbyl-3-carboxylphenylcarbamoyl) pyrimidine> -4-ylamino 1- (6'-1'-Hydroxyethyl) -1-methyl-carbapetylene-3-carbonyl] Prepared by (1R, 5S, 6S, 8R, 2S, 4S) -2- [1- (Allyloxycarbonyl) ) -2- (2- (dimethylaminocarbonyl) -3- (allyloxycarbonyl) phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1- The allyl protecting groups of the melylcarbapenem-3-carboxylic acid are deprotected as described in Example 2, and the product is purified as described in Example 2 with the difference. for the final products to be chromatographed on an HP20SS column. The appropriate aqueous fractions from the column were freeze-dried. The title compound is obtained

NMR (DMSO-d ₆ + CD _COOD?) (Mixture of rotamers): 1.17 (d 6H.), 1.75 (m, 2H), 2.65, 2.72 (2 x s overlapping m, 4H..). 3:00. 3.01 (2xs, overlapping m. 4H). 3.17 (dd. 1H), 3.41 (quintet 1H). 3.55 (m. 2H). 3.96 <m. 2H), 4.15 (dd. 1H). 7.43 (1, 1H), 7.68 (m. 1H). 8.20-8.40 (2xd. 1H).

The starting material was prepared as follows:

2-dimethylaminocarbonyl) -3-nitrobenzoic acid (g) was converted to the corresponding allyl ester as described in Example 1 for the preparation of the 3- (allyloxy) -5-aminobenzoic acid allyl ester. 0.88 g of allyl 2- (dimethylaminocarbonyl) 3-nitrobenzoic acid are obtained.

NMR _(DMSO-d6): 2.45 (s, 3H), 2.97 (s, 3H.), 4.79 (dd, 2H). 5.28-5.47 (m. 2H), 5.9-6,] (m. 1H), 7.81 (t, 1H), 8.28-8.4 (dq, 2H);

Mass spectrum (CI): 279 (MH &lt; + &gt;).

0.44 g of the allyl ester thus obtained are reduced with tin (II) chloride as described in Example 1. 0.41 g of allyl 2- (dimethylaminocarbonyl) -3-aminobenzoic acid is obtained in the form of a clear red oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.24 (s, 3H), 3.06 (s, 3H). 3.64 (br. 2H). 4.68 (dd, 2H), 5.17-5.37 (m.

2 H). 5.82-6.02 (m, 1H), 6.83 (dd, 1H), 7.09-6.85 (m, 1H), 7.37 (dd, 1H);

Mass Spec (Cl): 249 (MH) ⁺ .

0.39 g (1.4 mmol) of allyl 2- (dimethylaminocarbonyl) -3-aminobenzoic acid as described in Example 12, N- (Anoxycarbonyl) -2-ethoxy-1,2-dihydro- in the presence of quinoline is condensed with <2S, 4S) -4- (acetylthio) -1- (allyloxycarbonyl) -2-carboxypyrrolidine. 0.84 g of (2S, 4S) -1- (allyloxycarbonyl) -2- (2- (dimethylaminocarbonyl) -3- (allyloxycarbonyl) phenylcarbamoyl) pyrrolidine- 4-ylthioacetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , mixture of rotamers):

2.32 (s, 3H), 2.38 (broad m, partially distorted, 1H),

2.38 (broad m, partially distorted, 1H), 2.74, 2.76 (2xs and overlapping broad m, 4H), 3.11, 3.14 (2xs. 3H). 3.363.45 (m. 1H), 3.98-4.14 (m, 2H), 4.50 (dd. 1H), 4.56-4.79 (m. 4H), 5.16-5.44 (m, 4H), 5.93-6.06 (m, 2H), 7.45 (t, 1H), 7.81-7.86 (m, 1H), 8.33-8.41 (2xd, 1H). 6.80 (broad, 1H);

Nuclear Magnetic Resonance Spectrum (Cl): 504 (MH) ⁺ .

This thioacetate compound was converted to the corresponding thiol as described in Example 12.

0.73 g (1.47 mmol) of (1R, 5R, 6S, 8R) -6- (1-hydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid allyl ester 12 (2S.4S) -1- (Allyloxycarbonyl) -2- (2- (dimethylaminocarbonyl) -3- (allyloxycarbonyl) as described in Example 1 for the preparation of the protected carbapenem compound in acetonitrile (phenylcarbamoyl) pyrrolidin-4-ylthiol. 0.63 g of (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (allyloxycarbonyl) -2-1,2-dimethylaminocarbonyl--3- (allyloxy)] as a white solid. carbonyl (phenylcarbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

Nuclear Magnetic Resonance Spectrum (CDCl 3 / Rotamer mixture):

1.24 (d. 3H). 1.35 (2xd. 3H). 1.98 (broad, 1H). 2.34 (broad 1H). 2.73 (s, 3H). 3.11. 3.13 (2xs. 3H).

3.22-3.46 (m. 3H), 3.66-3.85 (m, 1H). 4.00-4.26 (m, 3H). 4.50 (t, 1H). 4.62 ^ 1.80 (m, 6H), 5.08-5.46 (m, 6H). 5.83-6.06 (m, 3H). 7.46 (td, 1H). 7.86 (d.

IH). 8.29 (m. 1H), 8.55 (broad, 1H); Mass spectrum (CI): 711 (MH) ⁺ .

Example 16 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (3-Carboxy-5- (acelantido) -phenylcarbamoyl) -pyrrolidin-4-yl-lio) -6- Preparation of (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid dipotassium salt

0.4 g (0.53 mmol) of (1R, 5S, 6S, 8R, 2S, 4'S) -2- (1- (4-nitrobenzyloxycarbonyl) -2- (3-carboxy-5-acetamidophenyl) Carbamoylpyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester in a solution of 0.2 g (1.39 mmol) of Meldrum in 20 ml of dimethylformamide acid and 40 mg (0.035 mmol) of tetrakis (triphenylphosphine) palladium. The reaction mixture was stirred for 1 hour at room temperature. To the mixture was added 20 ml of 1 M potassium phosphate buffer solution and 0.5 g of zinc powder, the mixture was kept at room temperature for 1 hour, then filtered through diatomaceous earth and the filtrate was adjusted to pH 7.5 with solid potassium carbonate.

I

EN 211 840 A9. The solution is filtered, the filtrate is concentrated under reduced pressure and the residue is purified by reverse phase chromatography (Nucleosil Cl8). Water is used as the eluent. Freeze-drying of the aqueous solution gave the title compound (78 mg, 28%). NMR (DMSO-d ₆ + CD ₃ COOD): 1.15 (d, 3H), 1.17 (d, 3H), 1.74 (m, IH), 2.06 (s, 3H) .

2.66 (m, 1H). 2.84 (m, 1H), 3.20 (dd, 1H), 3.40 (m,

2 H). 3.70 (m, 1H), 3.97 (m, 2H), 4.16 (dd, 1H).

7.92 (s, 1H), 7.94 (s, 1H), 8.19 (s, 1H).

The starting material was prepared as follows:

g (1.8 mmol) of (2S, 4S) -4- (acetylthio) -2-carboxy-1- (4-nitrobenzyloxycarbonyl) pyrrolidine and 0.53 g (3 mmol) of N- A solution of (ethoxycarbonyl) -2-ethoxy-1,2-dihydroquinoline in 70 ml of chloroform was stirred for 1 hour at room temperature. To the reaction mixture was added 0.53 g (2.7 mmol) of 3-acetamido-5-aminobenzoic acid and 0.7 ml (4 mmol) of diisopropylethylamine, which was stirred for 2 hours at room temperature and the solvent was evaporated. The crude product was purified by chromatography on an HP20SS column eluting with 80:20 methanol / water (0.68 g, 74%) (2S, 4S) -1 (4-nitrobenzyl). oxycarbonyl) -2- (3-carboxy-5-acetamido-phenylcarbamoyl) -pyrrolidin-4-yl-thiol NMR (DMSO-d ₆ + CD ₃ COOD): 2.05 (s. 3H). ), 2.05 (rn. IH). 2.75 (m. 1H). 3.20-3.80 (m.

2 H). 4.00 (m. 1H). 4.42 (m. 1H). 5.40 (wide s.

2H), 7.45-8.30 (m. 7H).

0.6 g (1.2 mmol) of (1R, 5S, 6S, 8R) -6- (1-hydroxy-ethyl) -1-methyl-2- (diphenyl-phosphoryloxy) -carbapenem-3-carboxylic acid 4-nitro- of the benzyl ester with 12 ml of dimethylformamide in the order indicated is 0.6 ml (3.4 mmol) of diisopropylethylamine. 0.6 g (1.2 mmol) of (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (3-carboxy-5-acetamido-phenylcarbamoyl) -pyrrolidin-4-yl-thiol. Tri-n-butylphosphine (0.6 mL, 2.4 mmol) and water (0.1 mL, 5.5 mmol) were added. After stirring overnight at 4 ° C, the volatiles were evaporated and the residue was purified by chromatography on HP20SS. The eluent was acetonitrile / water (40:60 by volume). The eluate was evaporated and the residue was freeze-dried. 0.8 g (88%) of (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5-acetamidophenyl) Carbamoyl) pyrrolidin-4-yl-lio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.15 (d, 3H), 1.17 (d, 3H.), 2.05 (s, 3H), '2.17 (m, IH )

2.81 (m, 1H), 3.26 (dd, 1H), 3.36 (td, 1H), 4.564.74 (m, 2H), 5.02-5.73 (m, 4H), δ , 91 (m, 1H),

7.47 (d, 1H), 7.68 (d, 1H), 7.85-7.99 (m, 3H),

8.20-8.29 (m. 2H).

Example 17 <1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 4-Acetamido-3-carboxyphenylcarbanoyl / pyrrolidin-4-ylthio) -6- (1- Preparation of hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid diphthalyl salt

This compound was prepared as described in Example 16 for (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (4-Nitrobenzyloxycarbonyl) -2- (4-acetamido-3-carboxylic acid). -phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester diisopropylethylamine.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.14 (d, 3H), 1.16 (d, 3H), 1.75 (m, IH), 2.07 (s, 3H) .

2.73 (m, 1H), 2.96 (dd, 1H), 3.21 (dd, 1H), 3.39 (m,

1H), 3.54 (dd, 1H), 3.78 (m, 1H), 3.96 (m, 1H),

4.08 (t, 1H), 4.18 (dd, 1H), 7.69 (dd, 1H), 8.18 (d.

IH). 8.42 (d, 1H);

Mass Spectrum (+ FAB): 571 (MH) ⁺ , (K-salt).

The starting material was prepared as follows:

From 2-Acetamido-5-aminobenzoic acid according to the procedure of Example 16 (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (4-acetamido-3-carboxyphenylcarbamoyl). Pyrrolidin-4-yl-thioacetate is prepared.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.95 (m, IH), 2.12 (s, 3H), 2.34 (s, 3H), 2.77 (m MA.).

3.32 (m. 1H), 3.93-4.50 (m, 3H), 5.04-5.32 (m.

2H), 7.47-8.42 (m. 7H).

The resulting QS-? 5S-1H-nitrobenzyloxycarbonyl-1- (4-acetamido-3-carboxyphenylcarbamoyl) -pyrrolidin-4-ylthioacetate was prepared as described in Example 16 (2S.4S). Converting to 1- (4-nitrobenzyloxycarbonyl) -2- (4-acetamido-3-carboxyphenylcarbamoyl) -pyrrolidin-4-yl-thiol.

(2S, 4S) -1- (4-Nylobenzyloxycarbonyl) -2- (4-acetamido-3-carboxyphenylcarbamoyl) -pyrrolidin-4-yl-ol as described in Example 16. R, 5R.6S.8R) -6- (Thydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid allyl ester (1R, 5R.6S.8R.2'S). 4'S) 2- (1- (4-Nitrobenzyloxycarbonyl) -2- (4-acetamido-3-carboxyphenylcarbamoyl) pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) 1-Methylcarbapenem-3-carboxylic acid allyl ester diisopropylethylamine salt was prepared.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.14-1.80 (m. 23H).

2.17 (s. 3H). 2.67 (m, 1H). 3.00-3.30 (m, 3H).

3.35-3.90 (m. 4H), 3.90-4.40 (m. 3H). 4.40-4.75 (m. 3H). 5.00-5.75 (m, 4H), 5.70-6.10 (m. 1H).

7.38-8.65 (ni. 7H).

Example 18 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (3-Carboxy-5- (methylsulphonylamino) -phenyl] -carbamoyl) -pyrimidine-4-yl-thio] -6- (1-hydroxy) ethyl) -] - methylcarbapenem-3-carboxylic acid dipotassium salt

This compound was prepared according to the procedure for Example 16 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5- methylsulfonamido (phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester. NMR (DMSO-d ₆ + CD ₃ COOD): 1.16 (d, 3H). 1.17 (d, 3H), 1.74 (m. 1H), 1.64 (m, 1H),

2.81 (dd, 1H), 3.01 (s, 3H), 3.20 (m, 1H), 3.40 (m.

2H), 3.68 (m, 1H), 3.96 (m. 2H), 4.17 (dd. 1H).

7.54 (s, 1H), 7.82 (s, 1H), 8.00 (s. 1H); Mass Spectrum (+ FAB): 607 (M + H) ⁺ , Monopotassium salt;

645 (M + H) ⁺ , dicalcium salt.

HU 211 840 A9

The starting material was prepared as follows:

From 3-Amino-5- (methylsulfonamido) -benzoic acid according to the procedure of Example 16, (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (3-carboxy-5- / methylsulfonamide) (phenyl-carbamoyl) -pyrrolidin-4-yl-thioacetate is prepared. NMR _(DMSO-d6 + CD, COOD): 2.00 (m, 1H), 2.30 (s, 3H), 2.84 (m, IH). 2.95 (s, 3H),

3.20-3.51 (m, 1H), 3.83-4.20 (m, 2H), 4.30-4.58 (m. 1H), 5.20 (m, 2H), 7.48-. 8.22 (m, 7H).

(25.45) From 1- (4-nitrobenzyloxycarbonyl) -2- (3-carboxy-5- (methylsulfonamido) -phenylcarbamoyl) -pyrrolidin-4-yl-thioacetate. (2S, 4S) -1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5-methylsulfonamido / phenylcarbamoyl) -pyrrolidin-4-ylthiol.

NMR (DMS0-d ₆ + CD _C00D?): 2.10 (IH in.). 2.78 On, 1H), 2.99 (s, 3H), 3.43 On, 1H).

3.68 (m. 1H). 4.05 (m. 1H). 4.42 (m, 1H). 5.135.32 (m. 3H). 7.50-8.82 (m, 7H).

(25.45) -1- (4-Nilobenzyloxycarbonyl) -2- (3-carboxy-5- (methylsulfonamido) -phenylcarbamoyl) -pyrrolidin4-yl-thiol and (1R, 5R, 6S) , 8R) -6- (1-Hydroxyethyl) -1-methyl-2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid allyl ester according to the procedure described in Example 16. 2'S.4'S) -2- [1- (Nitrobenzyloxycarbonyl) 2- (3-carboxy-5- (methylsulfonamido] -phenylcarbamoyl) -pyrrolidine η-4-yl-thio] -6 - (1-hydroxyethyl 1-1-methylcarbapenem-3-carboxylic acid allyl ester as white crystals NMR (DMSO-d ₆ + CD ₃ COOD): 1.20 (d, 3H), 1.22... (d. 3H), 1.96 (m. 1H). 2.83 (m. 1H).

3.00 (s. 3H). 2.26-3.57 (m. 3H). 3.87-4.28 (m. 4H).

4.42-4.76 (m. 3H). 5.08-5.42 On. 4H). 5.92 It is.

IH). 7.22-8.22 (m. 7H).

Example 19

HR.5S.6S.8R.2'S.4'S) -2-t- (3-Carboxy-5-sulfophenylcarbanoyl / pyrrolidin-4-yl-solution) -6-yl-hydroxyethyl) -1- Preparation of N-ethylcarbapenene-3-carbmisa [beta] disodium salt

0.5 g (0.56 mmol) of (IR, 5S.6S, 8R, 2'S, 4'S) -2- (1- (4-Nitro-benzyl) oxycarbonyl) -2- (3-carboxy-5-sulfophenylcarbamoyl) - of pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nitrobenzyl ester in 5 ml of dimethylformamide and 5 ml of water with stirring ml of 1 M sodium phosphate buffer solution and then 1 g of zinc powder. The reaction mixture was stirred for 1 hour and the pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. and purifying the residue by chromatography on a Nucleosil C-18 column. Water is used as the eluent. The appropriate eluate fractions were concentrated. then freeze-dried. 44 mg (12%) of the title compound are obtained.

NMR _(DMSO-d6 + CDjCOOD): 1.15 (d, 3H). 1.16 (d. 3H), 1.78 (m, 1H), 2.73 (m, 1H).

2.92 (in, 1H), 3.21 (dd in 1H), 3.40 (m, 1H). 3.48 (m.

IH). 3.75 (m. 1H) .3.97 (m, 1H), 4.O3 (m, 1H). 4.18 (m. 1H), 7.93 (s. 1H). 8.11 (s. 1H). 8.29 (s, 1H);

Mass Spectrum (-FAB): 576 (M-H), Monosodium salt; 598 (M-Hf, disodium salt.

The starting material was prepared as follows:

From 3-amino-5-sulfobenzoic acid according to the procedure described in Example 16, (2S, 4S) -1- (4-nitrobenzyloxycarbonyl) -2- (3-carboxy-5-sulfophenylcarbamoyl) - pinOlidin-4-yl-thioacetate was prepared.

NMR _(DMSO-d6 + CDjCOOD): 1.97 (m, IH), 2.30 (s, 3H), 2.80 (m, IH), 3.37 (m, IH).

3.86-4.15 (m. 2H), 4.46 (m, 1H), 5.05-5.28 (m.

2H), 7.46-9.25 (m, 7H).

From (2S, 4S) -1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5-sulfophenylcarbamoyl) pyrrole) din-4-ylthioacetate. (2S, 4S) -1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5-sulfophenylcarbamoyl) -pyrrolidin-4-yl-thiol.

NMR (DMSO-d _f + CDiCOOD) 1.25 (d. 3H). 1.27 (d. 3H). 2.07 (m. 1H). 2.70 (m. 1H).

3.4 (m. 1H). 3.67 (m, 1H), 3.99 (m, 1H). 4.49 (m.

IH). 5.07-5.30 (m. 2H), 7.47-8.40 (m, 7H).

(2S, 4S) -1- (4-Nitrobenzyloxycarbonyl) -2- (3-carboxy-5-sulfophenylcarbamoyl) -pyrrolidin-4-ylthiol and (1R, 5R. 6S.8R) -6- (1-Hydroxyethyl) -1-methyl-2- (diphenyl-1-phenyloxy) carbapenem-3-carboxylic acid 4-nitrobenzyl ester as described in Example 16 ( lR.5S.6S.8R.2''S.4'S) -2- (I- / 4-nitro-benzyloxy-carbonyl / 2- / 3-carboxy-5-sulfophenyl-carbamoyl / pyrrolidin-4 -I-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid 4-nilobenzyl ester. NMR (DMSO-d ₆ + _CD? COOD) 1.20 (d, 3H). 1.21 (d. 3H), 1.96 (m. 1H). 2.77 lm. 1H).

3.18-3.47 (m. 2H), 3.66-4.90 (6H). 5:04 to 5:50

0Π.4Η). 7.30-8.35 <m. 11H).

Example 20 15R.6S.8R, 2'S.4'S) -2-N- (3-Carboxyphenylcarbanyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) carbapenin-3 Preparation of -carboxylic acid disodium ester 0.185 g (0.296 mmol) of (5R, 6S, 8R, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / phenylcarbamoyl) pyrrolidine A solution of allyl -4-ylthio] -6- (1-hydroxyethyl) -carbapenem-3-carboxylic acid in 4 mL of dichloromethane with stirring at room temperature, in the order indicated, was 0.190 g (1.776 mmol) of N-methylaniline. Water (4 mL), sodium bicarbonate (100 mg) and tetrakis-triphenylphosphine (34 mg, 0.029 mmol) were added. After 10 minutes, the aqueous phase was separated and injected onto a preparative C18 HLPC column. The title compound (43 mg, 27% yield) NMR (DMSO-d ₆ + CD ₃ COOD): 1.16 (d, 3H), 1.81 (m MA.). 2.64 (m. 1H), 2.84 (m, 1H),

3.26 (m. 3H). 3.4 (m, 1H). 3.67 (m, 1H), 3.94 (m.

2H), 4.12 (m. 1H), 7.42 (l, 1H). 7.65 (d, 1H), 7.83 (d, 1H), 8.27 (s, 1H).

(5R, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-yl used as starting material -thio] -6- (1-hydroxyethyl) -carbapenem-3-carboxylic acid allyl ester was prepared according to the procedure of Example 1 in Example 4.

(2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-thiol and 126,780 A9. and Nos. 208,889. (5R, 6S, 8R) -6- (1-Hydroxyethyl) -2- (diphenylphosphoryloxy) carbapenem-3-carboxylic acid allyl ester. The desired compound was obtained in 67% yield.

Example 21 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-cyanophenylcarbanoyl] -pyrrolidin-4-ylthio) -6 - Preparation of disodium salt of (1-hydroxyethyl) -1-methylcarbapenene-3-carboxylic acid

358 mg (0.54 mmol) (1R, 5S, 6S, 8R, 2'S, 4'S-2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl) -5-cyanophenyl). carbamoyl) -pyrroid η-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester and 388 mg (2.7 mmol) of 2,2-dimethyl-1,3- To a solution of dioxane-4,6-dione in a mixture of dimethylformamide (8 mL) and tetrahydrofuran (4 mL) was added tetrakis (triphenylphosphine) palladium (62 mg, 0.054 mmol) under argon, and the solution was stirred under argon for 1.75 hours and The solvent was evaporated The residue was dissolved in a mixture of tetrahydrofuran (6 ml) and dimethylformamide (2 ml) and a solution of 2-ethylhexanecarboxylic acid sodium salt (298 mg, 1.77 mmol) in tetrahydrofuran (4 ml) was added. The precipitate was collected by centrifugation and the supernatant was removed and the product was washed with a suspension of tetrahydrofuran (4 ml) and diethyl ether (10 ml) followed by diethyl ether (20 ml). The crude product was dissolved in water (20 mL), adjusted to pH 7.4 with sodium bicarbonate, filtered and the filtrate chromatographed on HP20SS resin. 206 mg (70%) of the title compound were isolated from the appropriate fractions.

NMR _(DMSO-d6 + CD, COOD): 1.17 (d 6H.). 1.95 (m, partially distorted, 1H), 2.83 (m, 1H),

3.09 (dd. 1H). 3.25 (dd. 1H), 3.41 (quintet, 1H).

3.64 (dd. 1H). 3.88 (quintet 1H). 4.02 (quintet.

IH). 4.22 (dd, 1H), 4.31 <t. 1H), 8.00 (s, 1H). 8.28 (t, 1H), 8.46 (t. 1H);

Mass Spectrum (+ FAB): 523 (MH) ⁺ (Na salt).

The starting materials were prepared as follows:

Preparation of 3-cyano-5-nitrobenzoic acid

3.64 g (20 mmol) of 3-amino-5-nitrobenzoic acid are dissolved in 20 ml of concentrated aqueous hydrochloric acid. The solution was diluted with water (75 mL), cooled to 0 C and over 30 min

Add 1.38 g (20 mmol) of sodium nitrite in 10 mL of water. The pH of the mixture was adjusted to 6.2 with saturated aqueous sodium carbonate. To a solution of copper (II) sulfate pentahydrate (10 g, 42 mmol) in water (40 mL) was added a solution of potassium cyanide (10 g, 154 mmol) in water (20 mL), and the diazonium salt was added over 15 minutes. and the resulting mixture was refluxed for 40 minutes. The mixture was cooled, acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate (2 x 200 mL). The extracts were combined, washed with aqueous sodium dihydrogen phosphate solution, water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated. 3.6 g (94%) of 3-cyano-5-nitrobenzoic acid are obtained. Nuclear Magnetic Resonance Spectrum (DMSO-d6): 8.69 (t, 1H). 8.80 (t, 1H), 8.97 (t, 1H);

Mass Spectrum (-FAB): 191 (M-H) -;

Delta IR (Nujol): 2220 ^cm-1

The resulting 3-cyano-5-nitrobenzoic acid was allylated as described in Example 1, except that the eluent for chromatography was 5: 1 gasoline / ethyl acetate.

3-Cyano-5-nitrobenzoic acid allyl ester is obtained. Nuclear Magnetic Resonance Spectrum (DMSO-d6): 4.91 (dt, 2H).

5.39-5.53 (m, 2H), 5.99-6.19 (m. 1H), 8.78 (ι. 1H).

8.81 (t, 1H), 9.04 (1, 1H);

Mass Spectrum (+ FAB): 202 (M ⁺ ). 232 (M + NH ₄ ) ⁺ (both data refer to the amino compound obtained by reduction).

The above nitro compound was reduced as described in Example 1. Allyl 3-amino-5-cyanobenzoic acid is obtained; mp 112-113 "C.

NMR _(DMSO-D6): 4.79 (dt 2H.).

5.25-5.45 (m. 2H), 5.94-6.13 (overlapping m and broad.

1H), 7.10 (t. 1H), 7.37 (t. 1H). 7.48 (t, 1H); Mass Spectrum (+ FAB): 202 (M ⁺ ), 232 (M + NH ₄ F).

The resulting amine as described in Example 1 is condensed with proline carboxylic acid. The product was purified by chromatography on a gradient of dichloromethane / ethyl acetate (19: 1 to 9: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-V-5-cyanophenylcarbamoyl-D-pyrrohdin-4-ylthioacetate NMR Spectrum (CDCl 3): 2.33 (s. 3H), 2.59 (broad, 2H), 3.38 (dd, 1H), 3.97-4.17 (m, 2H), 4.56 (t. 1H). , 69 (d, 2H), 4.84 (d, 2H), 5.26-5.48 (m.

4H), 5.85-6.14 (m, 2H), 8.03 (br s, 1H). 8.18 (vol.

1H), 8.29 (br s, 1H), 9.69 (br, 1H): Mass Spectrum (+ FAB): 458 (MH) *. 480 (M + Na) +.

The thioacetate thus obtained was deacetylated as described in Example 1. (2S, 4S) -1- (Allyloxycarbonyl) 2- (3- (allyloxycarbonyl) -5-cyanophenylcarbamoyl) pyrrolidin-4-ylthiol.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.90 (d, 1H). 2.52 (br, 1H), 2.65 (br, 1H), 3.34-3.52 (m, 2H).

4.07 (dd, 1H), 4.54 (t, 1H), 4.69 (d, 2H), 4.84 (d.

2H), 5.27-5.47 (m, 4H), 5.87-6.11 (m, 2H). 8.01 (s.

1H), 8.21 (t, 1H), 8.28 (s, 1H), 9.56 (broad, 1H).

The thiol thus obtained is condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate (3: 2 to 2: 3). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -5-cyanophenylcarbamoyl) -pyrrolidine4 - allyl thio-6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.27 (d, 3H). 1.35 (d.

HU 211 840 A9

3H). 2.67 (very broad, 2H), 3.21-3.33 (overlapping m, 2H), 3.53 (broad, 1H), 3.83 (quintet, 1H), 3.93 (dd, 1H) , 4.20-4.31 (overlapping m, 2H). 4.54 (t. 1H), 4.63-4.86 (m, 6H), 5.21-5.47 (m. 6H), 5.82-6.11 (overlapping m and broad 3H). 8.05 (t, 1H), 8.33 (bs, 1H), 8.37 (bs, 1H), 9.35 (bs, 1H);

Spectrum (+ FAB); 665 (MH) ⁺ , 687 (M + Na) ⁺ .

Example 22 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- (3-Carboxy-5-methoxyphenylcarbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) Preparation of -1-Nethylcarbapenem-3-carboxylic acid disodium salt

This compound was prepared according to the procedure of Example 21.

NMR _(DMSO-d6 + CDjCOOD): 1.17 (d, 3H). 1.18 (d, 3H). 1.83 (m, partially distorted, 1H),

2.76 (quintet, 1H). 2.98 (dd, 1H), 3.22 (dd, 1H),

3.39 (quintet 1H). 3.56 (dd, 1H), 3.81 (overlapping s and m. 4H), 4.00 (quintet, 1H). 4.15. 4.18 (overlapping t and dd. 2H). 7.22 (t. 1H). 7.58 (t. 1H). 7.84 (t. 1H);

Mass Spectrum (-FAB): 505 (M-HT. Na salt).

The starting materials were prepared as follows:

3-Hydroxy-5-nitrobenzoic acid was methylated in the same manner as in the allylation step of Example 1. Dimethyl sulfate is used as the reagent instead of allyl bromide. Purification of the product by chromatography is unnecessary.

Methyl 3-methoxy-5-nitrobenzoic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 3.94 (s, 3H). 3.97 (s.

3H), 7.87 (1H). 7.90 (t. 1H). 8.44 (vol. JH).

To a solution of the thus-obtained ester (3.45 g, 16 mmol) in tetrahydrofuran (100 ml) was added 1N aqueous sodium hydroxide solution (25 ml) and the mixture was stirred for 5 hours at room temperature. The solvent was removed. and extracted three times with 60 ml of ethyl acetate each time. The organic extracts were combined, washed with aqueous sodium dihydrogen phosphate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The resulting 3-methoxy-5-nitrobenzoic acid was allylated as described in Example 1. with the difference. for purification by chromatography using 6: 1 gasoline / ethyl acetate (v / v) as eluent. Allyl 3-methoxy-5-nitrobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 3.95 (s, 3H). 4.87 (dt.

2H), 5.31-5.48 (m. 2H). 5.95-6.15 (m, 1H), 7.89 (l,

1H), 7.92 (t. 1H). 8.46 (1H);

Mass Spec (Cl): 237 (M ⁺ ), 255 (M + NH ₄ ) ⁺ .

This nitro compound is reduced as described in Example 1. 3-Amino-5-methoxybenzoic acid allyl ester is obtained.

NMR _(DMSO-d6): 3.72 (s, 3H), 4.50 (broad, 2H), 4.75 (dt, 2H), 5.25 to 5.43 (m, 2H ).

5.95-6.11 (m. 1H), 6.47 (t, 1H). 6.75 (t, 1H), 6.93 (t, 1H);

Mass spectrum (CI): 208 (MH ⁺ ).

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on a gradient of 5: 2 to 2: 1 gasoline / ethyl acetate. (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-5-methoxyphenylcarbamoyl) -pyrrolidin-4-ylthioacetal is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 2.32 (s, 3H), 2.59 (broad, 2H). 3.38 (dd, 1H), 3.85 (s, 3H), 4.02 (quintet 1H), 4.15 (dd, 1H), 4.55 (t, 1H), 4.68 (d) , 2 H).

4.81 (d. 2H). 5.22-5.46 (m, 4H), 5.83-6.13 (m, 2H), 7.35 (t, 1H), 7.58 (broad s, 1H), 7.64 (t, 1H) ).

9.12 (broad 1H);

Mass Spec (+ FAB): 463 (MH) ⁺ , 485 (M + Na) ⁺ .

The thioacetate thus obtained is deacetylated and then condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography on a gradient of dichloromethane / ethyl acetate (60:40 to 45:55). (JR, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3- (allyloxycarbonyl) -5-methoxyphenylcarbamoyl) pyrrolidine- 4,11-Thio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3-J; 1.25 (d. 3H). 1.37 (d.

3H). 2.64 (very broad 2H). 3.21-3.33 (overlapping m.

2H), 3.48 (broad, 1H), 3.80 (quintet, 1H). 3.85 (s.

3H). 4.01 (dd. 1H), 4.18-4.29 (overlapping m. 2H). 4.53 (l. 1H). 4.62-4.83 (m. 6H), 5.20-5.45 Int. 6H).

5.84-6.11 (overlapping m and broad. 3H). 7.25 (i.e. 1H.

7.63 (m. 2H). 8.90 (broad 1H);

Nuclear Magnetic Resonance (I + FAB): 670 (ΜΗΓ. 692 (M + NaT).

Example 23 (1R, 5S, 6S, 8R, 2'S, 4'S) -2-1,2-C15-Carboxy-2-methylsulfonyl-phenylcarbanoyl) -pyrrolidin-4-yl-thiol-6- <1-hydroxymethyl Preparation of ethyl bis-methylcarbapylene-3-carboxylic acid disodium salt

This compound was prepared as described in Example 1. The product is obtained in the form of diastereoisomers at the sulfoxide center.

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ -t-CD ₃ COOD): 1.18 (d, 6H). 1.87 (m. Partially distorted, 1H). 2.64-2.91.

2.82, 2.84 (overlapping m and 2xs. 5H). 3.21 (dd. 1H).

3.40 (quintet, 1H), 3.52 (dd, 1H), 3.71 (quintet, 1H).

1H), 4.01 (quintet. 1H), 4.01 (m. 1H), 4.18 (d.

1H), 7.83 (t, 1H), 7.94 (td, 1H). 8.45 (d, 1H); Nuclear Magnetic Resonance Spectrum (+ FAB): 560 (MH) ⁺ , Na salt: 582 (MH) ⁺ . disodium salt.

The starting materials were prepared as follows:

Preparation of 4- (methanesulfinyl) -3-nitrobenzoic acid

To a solution of 4.36 g (20 mmol) of 4- (methylthio) -3-nitrobenzoic acid in 200 ml of acetic acid was added 2.5 ml of 30% aqueous hydrogen peroxide solution (22 mmol of hydrogen peroxide) at room temperature. . After stirring for 4 days at room temperature, the excess hydrogen peroxide was quenched with sodium metabisulfite and the solvent was evaporated. The residue was purified by chromatography on silica gel as eluent

Methanol is used. 4.1 g (89%) of 4- (methanesulfinyl) 3-nitrobenzoic acid are obtained; m.p .; 238-239 ”C. Nuclear Magnetic Resonance Spectrum (DMSO-d6): 2.90 (s, 3H). 8.29 (d. 1H), 8.56 (dd, 1H), 8.68 (d. 1H); Mass Spectrum (-FAB): 229 (M-H).

This carboxylic acid is allylated as described in Example 1. except that chromatographic purification was not used because it proved to be unnecessary. Allyl 4- (methanesulfinyl) -3-nitrobenzoic acid is obtained; 119-121 ° C.

NMR _(DMSO-d6): 2.91 (s, 3H), 4.91 (dt 2H.). 5.29-5.50 (m, 2H), 5.99-6.18 (m, 1H),

8.34 (d, 1H), 8.61 (dd, 1H), 8.69 (d, 1H).

The resulting nitro compound is reduced as described in Example 1. 3-Amino-4- (methanesulfinyl) -benzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.92 (s, 3H), 4.82 (dt,

2 H). 5.17 (broad 2H), 5.28-5.46 (m, 2H), 5.966.11 (m. 1H). 7.30 (dd. 1H), 7.41 (m, 2H); Mass Spectrum (EI): 223 (MO) ⁺ . 239 (M ⁺ ).

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography, eluting with a gradient gradient of 3: 2 to 1: 1 hexane: ethyl acetate. (2S, 4S) -1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2- (melanesulfinyl) -enylcarbamoyl) -pyrrolidin-4-yl-lio- acetate.

NMR (DMSO-d ₆ 100 ° C.): 1.98 <m. IH). 2.32 (s. 3H). 2.73 (s. 3H>. 2.86 (m, partially distorted. 1H). 3.36 (m. 1H). 3.91-4.10 (overlapping m. 2H). 4.48 (dd. 1H) 4.53 (m. 2H) ), 4.86 (d. 2H), 5.11-5.49 (m. 4H), 5.80-5.97 (m. 1H), 6.01-6.15 (ni. 1H> .8.09 (s. 2H), 8.35 (s, 1H);

Mass Spectrum (+ FAB): 495 (ΜΗΓ.

This lyoacetate is deacetylated. and then condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with gradient ethyl acetate / isopropanol (100: 0 to 98: 2). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2- (methanesulfinyl) phenyl) Carbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarboxylate is obtained in the form of non-3-carboxylic acid allyl.

NMR _(DMSO-d6, mixture of rotamers):

1.18 (d, 6H), 1.99 (broad, 1H), 2.80 (overlapping s and m,

5H). 3.25 (solvent overlap. 2H). 3.54 (m, 1H),

3.90-4.18 (m, 3H), 4.15 (dd. 1H), 4.55 (m, 4H),

4.85 (d. 2H). 5.06 (d, 1H), 5.14-5.46 (m. 6H),

5.79-6.13 (m, 3H), 7.80-8.05 (m, 2H), 8.12 (m,

IH). 10.10 (m. 1H);

Mass Spectrum (+ FAB): 702 (MH) ⁺ .

Example 24 (} R. 5S. 6S, 8R, 2'S, 4'S) -2-1,2- (3-Carboxy-5-methanesulfinyl-phenylcarbamoyl) -pyrrolidin-4-yl-thio] -6- ( Preparation of the disodium salt of T-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid

This compound was prepared according to the procedure of Example 21.

NMR _(DMSO-d6 + CDjCOOD): 1.16 (d, 3H), 1.18 (d, 3H). 1.75 (quintet, 1H), 2.63 < m.

1H), 2.79 (dd, 1H), 3.20 (overlapping s and m. 4H). 3.38 (m, 2H), 3.64 (quintet, 1H), 3.95 (m, 2H). , 4.14 (dd.

IH). 8.09 (t, 1H), 8.44 (m, 2H);

Mass Spectrum (-FAB): 574 (M-H), Na salt.

The starting materials were prepared as follows:

Preparation of 3- (methylthio) -5-nitrobenzoic acid

A solution of 3-amino-5-nitrobenzoic acid (1.82 g, 10 mmol) in concentrated sulfuric acid (1.9 mL) was diluted with water (10 mL) and cooled to 5 ° C. A solution of sodium nitrite (0.7 g, 10 mmol) in water (3 mL) was added and the mixture was stirred for 30 minutes. The cold diazonium salt solution was added to a suspension of thiomethyl copper (I) at 3 ° C and the mixture was stirred for 45 minutes. The fly was then extracted with ethyl acetate (5 x 60 mL). The organic layers were combined with an aqueous solution of sodium dihydrogen phosphate. water, followed by brine, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated. 1.77 g (83%) of 3- (methylthio) -5-nitrobenzoic acid are obtained.

NMR _(DMSO-d6): 2.63 (s, 3H.). 8.10 (t, 1H). 8.21 (t, 1H). 8.32 (vol. 1H), 13.68 (broad.

IH);

Mass Spectrum (-FAB): 213 (M-H).

This carboxylic acid was allylated as described in Example 1, except that the chromatography was carried out using 6: 1 gasoline / ethyl acetate. 3- (Methyl-lio) -5-nitrobenzoic acid allyl is obtained.

Nuclear Magnetic Resonance Spectrum (CDCF): 2.60 (s. 3H). 4.87 idt.

2H), 5.32-5.49 (m. 2H). 5.93-6.07 (m. 1H). 8.20 (m, 2H), 8.57 (1, 1H);

Mass Spectrum (EI): 253 (M ⁺ ).

3-1 Preparation of Allyl Methylsulfonyl IS-Nitrobenzoic Acid

A solution of 1.12 g (4.4 mmol) of 3- (methylthio) -5-nitrobenzoic acid ester in 30 ml of methanol with stirring. At 2 ° C, a solution of 8.13 g of potassium peoxypro-monopersulphal (KHSO 3 - KHSO 3 - K 3 SO 4) in 25 ml of water is added slowly. After stirring for a further 4 hours, the mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate, and the crude product was isolated. The crude product was purified by chromatography on silica gel using gradient gradient gasoline / ethyl acetate (3: 1 to 2: 1) as the eluent to give 0.72 g (59%) of 3- (methylsulfonyl) -5-nitrobenzoic acid. The alpha-1 l ester is obtained.

NMR _(DMSO-d6): 3.44 (s, 3H). 4.94 (dt, 2H), 5.32-5.53 (m, 2H), 6.01-6.25 (m. 1H).

8.78 (t, 1H), 8.89 (t, 1H), 8.91 (t, 1H).

This nitro compound is reduced as described in Example 1. 3-Amino-5- (methanesulfonyl) -benzoic acid ester is obtained.

I

HU 211 840 A9

NMR _(DMSO-d6): 3.15 (s, 3H). 4.80 (dt, 2H), 5.26-5.47 (m, 2H), 5.95-6.15 (m and overlapping 3H), 7.29 (t, 1H). 7.47 (t, 1H), 7.51 (t, 1H). This amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography, eluting with a gradient of 2: 1 and 1: 1 gradient hexane / ethyl acetate. (2S, 4S) -1- (Allyloxycarbonyl) -2- (3- (allyloxycarbonyl) -57-methanesulfonyl-phenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 2.34 (s. 3H), 2.48 (m.

1H), 2.62 (m, 1H), 3.17 (s'3H), 3.41 (dd. 1H), 4.03 (quintet 1H), 4.15 (dd, 1H) .4, 58 (dd, 1H), 4.71 (d.

2 H). 4.84 (dt, 2H), 5.27-5.47 (m, 4H), 5.88-6.14 (m, 2H), 8.23 (broad s 2H), 8.37 (t , 1H). 9.69 (broad, 1H):

Mass Spectrum (+ FAB): 511 (MH) ⁺ , 533 (M + Na) *.

This thioacetate was deacetylated and then condensed with the carbapenem phosphate compound as described in Example 1. The product is purified by chromatography. eluting with a gradient gradient of dichloromethane / ethyl acetate (55:45 to 20:80). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3- (allyloxycarbonyl) -5- (methanesulfonyl) -1- phenyl-1-carbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.24 (d, 3H). 1.36 (d.

3H). 2.54 (br. 1H, 2.66 (br, 1H). 3.12 (s.

3H). 3.19-3.22 (overlapping m, 2H). 3.54 (broad 1H).

3.87 (quintet 1H). 3.94 (dd. 1H). 4.25. 4.29 (overlapping quintet and dd. 2H). 4.55 (t. 1H). 4.65-4.80 (m. 4H). 4.85 (d. 2H). 5.20-5.66 (m. 6H>. 5.86-6.12 (overlapping m and broad. 3H). 8.31 (broad 1H), 8.43 (broad 1H). 8.52 (broad 1H). 9.40 (broad 1H). IH);

Mass Spectrum (+ FAB): 718 (MH) ⁺ . 740 (M + Na) ⁺ .

Example 25 (IK.5S.6S.8R.2'S.4'S) -2- [2- (3-Carboxy-5-trifluoro- (methyl) -phenylcarbanoyl) -pimidin-4-yl-thio] -6 Preparation of (dihydroxyethyl) -1-methylcarbapenein-3-carboxylic acid dihydrate salt

This compound was prepared in Example 2 using the lein method.

NMR _(DMSO-d6 + CD, COOD): 1.16 (d, 6H). 1.92 (m. Partially distorted. 1H), 2.77 (m. Partially distorted, 1H), 3.00 (dd, 1H), 3.21 (dd, 1H).

3.37 (quintet, 1H), 3.59 (quintet, 1H), 3.80 (quintet, 1H), 3.97 (quintet, 1H), 4.20 (m. 2H), 7.91 (broad s. 1H) . 8.27 (broad s, 1H). 8.44 (bs, 1H);

Mass Spectrum (-FAB): 542 (Μ-ΗΓ, acid, 564 (ΜΗ) ^- . Sodium salt.

The starting materials were prepared as follows:

3-Nilro-5- (trifluoromethyl) benzoic acid is allylated as described in Example 1. The raw stuff would be reasonably pure. Thus, it does not require chromatography. Allyl 3-nitro-5-trifluoromethyl-benzoic acid is obtained. NMR _(DMSO-d6): 4.91 (dt 2H.).

5.30-5.51 (m. 2H), 5.99-6.20 (m, 1H), 8.58 (broad s, 1H), 8.77 (broad s, 1H), 8.84 ( t, 1H);

Nuclear Magnetic Resonance Spectrum (Cl): 275 (M ⁺ ), 293 (M + NH ₄ ) ⁺ .

The nitro compound thus obtained was reduced as described in Example 2. 3-Amino-5- (trifluoromethyl) -benzoic acid allyl ester is obtained, which does not require purification by chromatography.

NMR (DMSO-d _e): 4.78 (dt, 2H). 5.24-5.43 (m, 2H). 5.93-6.13 (m, 1H), 7.08 (t, 1H).

7.27 (broad 1H). 7.44 (t, 1H);

Tom spectrum (Cl): 245 (M ⁺ ), 263 (M + NH ₄ ) *.

The resulting amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (10: 0 to 9: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3- (allyloxycarbonyl) -5- (trifluoromethyl) phenylcarbamoyl) pyrrolidin-4-ylthioacetate we get.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.33 (s. 3H). 2.59 (ni. 2H). 3.39 (dd. 1H). 4.04 (quintet, 1H). 4.14 (dd. 1H). 4.58 (t. 1H). 4.62 (dt, 2H). 4.85 (d. 2H). 5.23-5.48 tm. 4H). 5.84-6.14 (m. 2H), 8.03 (broad s. 1H). 8.23 (broad s, 2H). 9.60 (broad 1H);

Spectrum (+ FAB): 501 (MH) ⁺ . 523 (M + Naf) This thioacetate was deacetylated and then condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with a gradient of dichloromethane (10: 1 to 1: 9). (ethyl acetate mixtures). (1R, 5S.6S.8R.2'S.4'S) -2- [T (AU) 1-Oxycarbonyl] -2- (3-allyloxycarbonyl) -5- / trifluoro -methyl-phenyl-carbamoyl-pyrrolidin-4-ylthio] -6- (1-hydroxyethyl-ε-1-methylcarbapenz-3-carboxylic acid allyl ester) NMR (DMSO-d ₆ + CD iCOOD): 1.21 (d, 6H), 2.05 (broad 1H), 2.85 (broad 1H), 3.29 (dd 1H), 3.44 (dd, 1H), 3.51 (quintet, 1H) 3.93 (broad) (J H) 4.05-4.18 (m, 2H), 4.27 (dd. 1H).

4.43-4.71 (overlapping m. 5H), 4.85 (d. 2H). 5.16-5.46 (m, 6H). 5.70-6.16 (m. 3H). 7.94 (broad s. 1H).

8.37 (broad s. 1H). 8.53 (bs, 1H);

Mass Spectrum (+ FAB): 708 (MH) ⁺ . 730 (M + Naf.

Example 26 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [5-Carboxy-2-methoxy-phenylcarbamoyl] -pyrrolidyl-4-yl-thio) -6- ( Preparation of 1-Hydroxyethyl) -} - Methyl Carbapeitem-3-Carboxylic Acid Disodium Salt

This compound was prepared according to the procedure of Example 1.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.20 (d 6H.). 1.93 (m, partially distorted, 1H), 2.86 (quintet, 1H). 3.02 (dd. 1H), 3.26 (dd, 1H), 3.44 (quintet, 1H), 3.68 (dd, 1H), 3.84 (quintet, 1H). 3.95 (s. 3H); 4.03 (quintet. 1H); 4.22 (dd, 1H). 4.34 (l, 1H).

7.13 (d. 1H). 7.78 (dd, 1H), 8.25 (d, 1H);

Mass Spectrum (+ FAB): 528 (MH) ⁺ , Sodium salt; 550 (MH) ⁺ , disodium salt.

The starting materials were prepared as follows:

HU 211 840 A9

4-Methoxy-3-nitrobenzoic acid was allylated as described in Example 1. The product is pure without further purification by chromatography. The allyl 3-nitro-4-methoxybenzoic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.03 (s. 3H), 4.83 (dt,

2 H). 5.29-5.46 (m. 2H), 5.93-6.14 (m, 1H), 7.14 (d, 1H). 8.24 (dd, 1H), 8.52 (d, 1H); Mass spectrum (CI): 237 (M ⁺ ), 255 (M + NH ₄ ) ⁺ .

Reduce this nitro compound as described in Example 2. 3-Amino-4-methoxybenzoic acid allyl ester is obtained, which is purified without further chromatography.

Nuclear Magnetic Resonance Spectrum (CDCl3): 3.72 (br, 2H), 3.90 (s, 3H). 4.77 (dt, 2H). 5.24-5.43 (m, 2H), 5.95-6.10 (m, 1H), 6.79 (d. 1H). 7.41 (d, 1H), 7.5O (dd. 1H); Mass spectrum (CI): 208 (MH ⁺ ).

This amine compound is condensed with proline carboxylic acid as described in Example 4. The product was purified by flash chromatography on silica gel eluting with a gradient of dichloromethane / diethyl ether (10: 0 to 4: 1).

(2S, 4S) -1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2methoxyphenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 2.33 (s. 3H). 2.51 (broad 1H). 2.66 (broad, 1H). 3.41 (dd, 1H). 3.93 (s. 3H). 4.01 (quintet 1H). 4.17 (dd, 1H). 4.55 (I.

IH). 4.64 (d. 2H). 4.80 (dt. 2H). 5.18-5.44 (m, 4H).

5.81-6.14 (overlapping m and broad. 2H). 6.91 (d, 1H),

7.84 (dd. 1H). 8.90 (broad 1H), 9.01 (d. 1H); Mass Spectrum (+ FAB): 463 (MH) ⁺ . 485 (M + Naf.

This thioacetate compound is deacetylated and the product condensed with the carbapenem phosphate compound as described in Example I. Its products are purified by chromatography, eluting with a gradient gradient of pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2-methoxyphenylcarbamoyl) -pyr rolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.23 (d, 3H). 1.36 (d.

3H). 2.52 (broad 1H). 2.66 (broad 1H). 3.22 (dd.

IH). 3.28 (quintet, 1H), 3.44 (dd, 1H), 3.83 (quintet,

IH). 3.93 (s, 3H), 4.09 (m, 1H). 4.19-4.31 (overlapping m,

2 H). 4.53 (t, 1H), 4.65 (m, 4H), 4.81 (d, 2H), 5.195.45 (m, 6H). 5.83-6.11 (m, 3H), 6.91 (d, 1H), 7.83 (dd, 1H), 8.79 (broad, 1H), 9.04 (d, 1H); Mass Spectrum (+ FAB): 670 (MH) ⁺ , 692 (M + Na) ⁺ .

Example 27 (IR.5S.6S.8R, 2'S.4'S) -2- (2- [3-Carboxy-4-ethoxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (I-) hydmxylil) -N-methylcarbapenene-3-carboxylic acid disodium salt

This compound was prepared according to the procedure described in Example 2. except that dimethylsulfoxide is used in place of dimethylformamide.

NMR _(DMSO-D6 + CD, COOD): 1.17 (d, 6H). 1.83 (m. Partially distorted, 1H), 2.75 (quintet, 1H), 2.97 (dd, 1H), 3.23 (dd, 1H), 3.40 (quintet, 1H), 3, 56 (dd. 1H), 3.82 (s + m, 4H), 3.99 (quintet, 1H), 4.12 (t, 1H), 4.19 (dd, 1H), 7.09 (d) , 1H).

7.75 (dd, 1H), 7.95 (d, 1H);

Mass Spectrum (+ FAB): 528 (MH) ⁺ , Monosodium salt.

550 (MH) ⁺ , disodium salt.

The starting materials were prepared as follows:

2-Methoxy-5-nitrobenzoic acid was allylated as described in Example 1. The product is pure without further purification by chromatography. 2-Methoxy-5-nitrobenzoic acid allyl ester is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.03 (s, 3H), 4.85 (dt.

2H), 5.30-5.49 (m. 2H), 5.95-6.14 (m, 1H), 7.08 (d. 1H), 8.48 (dd, 1H), 8.72 (d) , 1H); Mass spectrum (CI): 238 (MH) ⁺ , 255 (M + NH ₄ ) ⁺ .

This nitro compound was prepared as described in Example 2

Reduction to 5-amino-2-methoxybenzoic acid allyl ester The product is pure without further chromatography.

Nuclear Magnetic Resonance Spectrum (CDCl3): 3.39 (broad, 2H), 3.83 (s. 3H), 4.80 (dt, 2H), 5.23-5.47 (m. 2H), 5.94-6.13 ( m, 1H). 6.83 (d, 2H), 7.18 (t, 1H);

Mass spectrum (CI): 208 (MH ⁺ ).

This amine compound is condensed with proline carboxylic acid as described in Example 4. The product was purified by chromatography on silica gel eluting with a gradient gradient of dichloromethane / diethyl ether (10: 0 to 4: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-4-methoxyphenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 2.32 (s. 3H). 2.58 (broad, 2H). 3.39 (dd, 1H). 3.89 (s, 3H). 4.02 (quintet, 1H), 4.13 (dd. 1H). 4.53 (t, 1H), 4.66 (dl. 2H). 4.80 (dt. 2H), 5.23-5.48 <m. 4H). 5.84-6.13 lm. 2 H). 6.94 (d. 1H), 7.80 (m, 2H), 8.94 (broad 1H):

Mass spectrum (CI): 463 (MH ⁺ ).

This thioacetate was deacetylated and condensed with carbapenem as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (LR, 5S, 6S, 8R, 2'S, 4'S) -2- [l- (-allyloxycarbonyl) -2- (3 / allyloxy carbonyl / -4-methoxy-phenylcarbamoyl) -pyrrolidine -4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.25 (d, 3H), 1.36 (d.

3H), 2.65 (broad, 2H), 3.25 (dd, 1H), 3.28 (quintet).

1H), 3.47 (broad, 1H), 3.79 (quintet, 1H), 3.89 (s.

3H), 4.01 (dd, 1H), 4.18-4.29 (overlapping m, 2H), 4.51 (t, 1H), 4.66 (m. 4H), 4.79 (dt. 2H) , 5.19-5.46 (m,

6H), 5.84-6.11 (m, 3H), 6.95 (d, 1H), 7.79-7.87 (m, 2H), 8.70 (broad, 1H);

Mass Spectrum (+ FAB): 670 (MH) ⁺ , 692 (M + Naf).

Example 28 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-2-methoxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1- hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid disodium salt

This compound was prepared as described in Example 2

EN 211 840 A9 ahead. except that dimethylformoxide is used instead of dimethylformamide.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.18 (d 6H.). 1.85 (partially distorted m, 1H), 2.66-2.86 (overlapping m. 2H), 3.21 (dd, 1H), 3.41 (quintet, 1H).

3.52-3.72 (overlapping m, 2H), 3.82 (s, 3H), 3.99 (quintet, 1H), 4.08 (dd, 1H), 4.17 (dd, 1H), 7.17 (t. 1H).

7.45 (dd, 1H), 8.41 (dd, 1H);

Mass Spectrum (+ FAB): 528 (MH) * monosodium salt.

550 (MH) ⁺ disodium salt.

The starting materials were prepared as follows:

2-Hydroxy-3-nitrobenzoic acid was methylated by the esterification method described in Example 1, but using methyl iodide instead of allyl bromide. Purification of the product by chromatography is unnecessary. Methyl 2-methoxy-3-nitrobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (DMSO-d6): 3.88 (s, 3H). 3.90 (s, 3H). 7.44 (t. 1H). 8.04 (dd, 1H), 8.12 (dd, 1H); Mass spectrum (CI): 212 (MH +). 229 (M + NH ₄ ) *.

3.45 g (16 mmol) of the ester thus obtained in Example 22 are hydrolyzed. with the difference that dimethylsulfoxide is used as solvent instead of tetrahydrofuran. 2-Methoxy-3-nitrobenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (DMSO-tL): 3.89 (s. 3H). 7.40 (t, 1H). 8.01 (dd. IH), 8.06 (dd. IH); Mass spectrum (CI): 215 (M + NH ₄ ) *.

The carboxylic acids thus obtained were allylated as described in Example 1. The product obtained is of sufficient purity for further tilting without chromatography.

An allyl ester of 2-methoxy-3-nitrobenzoic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.00 (s, 3H). 4.86 (dl.

2Hi. 5.31-5.50 (m. 2H). 5.96-6.16 (m. 1H). 7.27 (d, 1H). 7.92 (dd. 1H), 8.06 (dd. 1H): Mass Spectrum (Cl): 238 (MH) +, 255 (M + NH ₄₎ *.

This nitro compound is reduced as described in Example 1. 3-Amino-2-meloxybenzoic acid allyl ester is obtained which is sufficiently pure for further processing without chromatography.

Nuclear Magnetic Resonance Spectrum (CDCl3): 3.86 (s, 3H), 3.92 (broad, 2H). 4.82 (dt. 2H). 5.26-5.49 (m. 2H).

5.96-6.16 (m, 1H). 6.91 (dd. 1H), 7.00 (t, 1H). 7.23 (dd. 1H):

Mass spectrum (CI): 208 (MH +). 225 (M + NH ₄ ) *.

This amine compound is condensed with proline carboxylic acid as described in Example 4. (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -2-methoxyphenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDC13): 2.30 (s, 3H), 2.53 (broad 1H), 2.65 (broad 1H), 3.41 (dd 1H), 3.86 (s, 3H) . 4.04 (quintet, 1H), 4.16 (dd, 1H). 4.58 (vol.

IH). 4.66 (d, 2H). 4.83 (dl, 2H), 5.20-5.47 (m, 4H).

5.83-6.13 (overlapping m and broad, 2H), 7.16 (t, 1H).

7.60 (dd, 1H). 8.57 (dd, 1H), 9.15 (broad, 1H); Mass Spectrum (+ FAB): 463 (MH) *, 485 (M + Na) *.

This was deacetylated with its thioacetate compounds as described in Example 1 and then condensed with the carbapenem-1'phosphal compound. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -2-methoxyphenylcarbamoyl) pyrrolidine -4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.24 (d, 3H), 1.35 (d,

3H), 2.53 (br, 1H), 2.68 (br, 1H), 3.24 (dd,

1H), 3.28 (quintet, 1H), 3.43 (broad, 1H), 3.80 (quintet, 1H), 3.83 (s, 3H), 4.12 (m, 1H), 4.194.29 (overlapping m , 2H), 4.57 (t, 1H), 4.64 (m, 4H),

4.83 (d, 2H), 5.18-5.48 (m, 6H). 5.81-6.14 {m.

3H), 7.17 (t, 1H), 7.61 (dd, 1H), 8.56 (dd, 1H). 9.02 (wide, 1H):

Mass Spectrum (+ FAB): 670 (MH) *, 692 (M + Na) *.

Example 29 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (5-Carboxy-2-methyl-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1) -hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid dihydrogen salt

This compound was prepared as described in Example 2. except that dimethylsulfoxide is used in place of dimethylformamide.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.19 (d, 6H). 1.88 (m, partially distorted. 1H). 2.31 (s 3H).

2.77 (dt. 1H). 2.93 (dd, 1H). 3.22 (dd. 1H). 3.42 (quintet, 1H). 3.57 (dd, 1H). 3.77 (quintet, 1H).

4.01 (quintet 1H), 4.16 (1H), 4.19 (dd 1H). 7.35 (d. 1H). 7.69 (dd, 1H), 8.39 (d, 1H); Mass Spectrum (+ FAB): 512 (MH) * monosodium salt.

534 (MH) * disodium salt. 556 (M + Na) * disodium salt.

The starting materials were prepared as follows:

4-Methyl-3-nitrobenzoic acid was allylated as described in Example 1. Purification of the product by chromatography is unnecessary. Allyl 4-methyl-3-nitrobenzoic acid is obtained.

NMR _(DMSO-d6): 2:59 (s 3Hi 4.84 (dt 2H) 5:27 to 5:47 (m, 2H) 5,96-6.16 (m IH).......

7.67 (d. 1H). 8.16 (dd. 1H), 8.44 (d, 1H); Mass spectrum (EI): 222 (MH +).

This nitro compound was reduced as described in Example 2, except that methanol was used as the solvent. The product was obtained without further chromatography without purification and gave 3-Anuno-4-methylbenzoic acid allyl ester of pure purity (DMSO-d ₆ ): 2.10 (s, 3H). 4.74 (dt, 2H). 5.15 (broad 2H), 5.22-5.43 (m. 2H).

5.93-6.12 (m, 1H), 7.04 (d. 1H), 7.11 (dd, 1H), 7.28 (d, 1H):

Mass spectrum (CI): 192 (MH +). 209 (M + NH ₄ ) *.

This amine compound is condensed with proline carboxylic acid as described in Example 4. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (10: 0 to 9: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2-methylphenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained. NMR _(DMSO-d6, mixture of rotamers):

HU 211 840 A9

1.97 (quintet, 1H), 2.26 (s, 3H), 2.34 (s, 3H). 2.80 (br, 1H), 3.30 (br, 1H), 3.93-4.08 (br,

2H), 4.53 (broad, 1H), 4.80 (dt, 2H), 5.10-5.44 (overlapping m and broad, 4H), 5.78-6.13 (overlapping m and broad, 2H), 7.38 (d, 1H), 7.72 (dd, 1H), 7.94 (broad, 0.5H), 8.01 (broad, 0.5H), 9.61 (broad, 0 , 5H), 9.67 (broad, 0.5H);

Tom spectrum (CI): 447 (MH ⁺ ), 464 (M + NH ₄

This thioacetate compound was deacetylated as described in Example 1 and then condensed with the carbapenem phosphate compound. The product is purified by chromatography. eluting with a gradient gradient of dichloromethane / ethyl acetate (1: 0 to 1: 1). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2-methylphenylcarbamoyl) pyrrole Allyl ester of n-4-yl-thio] -6- (1H-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid is obtained.

NMR (DMSO-d ₆ + CD ₃ COOD, mixture of rotamers): 1.16 (d, 3H.), 1.18 (d, 3H), 1.98 (quintet MA.). 2.27 (s, 3H), 2.86 (broad, 1H), 3.27 (dd, 1H). 3.33 (t. 1H). 3.56 (quintet, 1H), 3.95 (quintet, 1H). 4.02 (dd, 1H), 4.15 (quintet. 1H), 4.27 (dd. 1H). 4.48-4.70 (overlapping m. 5H), 4.80 (d, 2H). 5.10-5.45 (m and overlapping 6H). 5.81-6.14 (overlapping m and broad. 3H). 7.38 (d, 1H), 7.75 (dd, 1H). 8.01 (br. 0.5H), 8.07 (br, 0.5H). 9.60 (broad 1H);

Mass Spectrum (+ FAB): 654 (MH +, 676 (M + Naf).

Example 30 tR5S.6S.8R.2'S.4'S) -2- (2- / 3-Carboxy-4-methylphenylcarbanoyl / pyrrolidyl-4-ylthio) -6- (1 -hydroxyethyl) -1-methcarbapenem-3-carboxylic acid disodium salt

This compound was prepared as described in Example 2. except that dimethylformoxide is used instead of dimethylformamide.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.15 (d, 3H.). 1.16 (d, 3H), 1.78 (dt, 1H), 2.48 (s, 3H).

2.60 (dl, 1H). 2.90 (dd. 1H), 3.21 (dd, 1H), 3.39 (quintet, 1H), 3.49 (dd, 1H), 3.73 (quintet, 1H),

3.99 (quintet, 1H), 4.10 (t, 1H), 4.17 (dd, 1H), 7.23 (dd 1H), 7.70 (dd, 1H), 8.12 (d, 1H); Mass Spectrum (+ FAB): 512 (MHf monosodium salt,

534 (MHf disodium salt, 556 (M + Naf disodium salt.

The starting materials were prepared as follows:

2-Methyl-5-nitrobenzoic acid is allylzinc as described in Example 1. 2-Methyl-5-ni (allyl-benzobenzoic acid ester) is obtained which does not require chromatographic purification.

NMR _(DMSO-d6): 2.65 (s, 3H), 4.84 (dt, 2H), 5.28 to 5.47 (m, 2H), 5.99 to 6.18 ( m, 1H),

7.65 (d. 1H), 8.31 (dd, 1H), 8.57 (d, 1H); MS (CI): 222 (MH +, 299 (M + _NH4 f.

This nitro compound was reduced as described in Example 2, except that methanol was used as the solvent. An allyl of 5-amino-2-methylbenzoic acid is obtained which is sufficiently pure for further use without chromatography.

Nuclear Magnetic Resonance Spectrum (DMSO-d6): 2.33 (s, 3H), 4.73 (dt, 2H), 5.18 (broad, 2H), 5.23-5.44 (m, 2H). .

5.93-6.12 (m, 1H), 6.68 8dd, 1H), 6.95 8d. IH).

7.12 δd, 1H);

MS (CI): 192 (MH +, 209 (M + _NH4 f.

This amine compound is condensed with proline carboxylic acid as described in Example 4. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (10: 0 to 9: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-4-methylphenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. NMR _(DMSO-d6, mixture of rotamers):

1.91 (br m, 1H), 2.33 (s, 3H), 2.76 (br m).

1H), 3.28 (overlapping s and m, 4H), 4.00 (broad m, 2H).

4.38 (t, 1H), 4.51 (broad, 2H), 4.78 (dt, 2H), 5.015.46 (overlapping m and broad, 4H), 5.68-6.16 (overlapping m and broad, 2H), 7.27 (d, 1H), 7.72 (dd, 1H). 8.11 (br, 0.5H), 8.05 (br, 0.5H), 10.17 (br, 1H);

Spectrum (+ FAB) 447 (MH + 469 (M +

This thioacetate compound was deacetylated as described in Example 1 and then condensed with the carbapenem phosphate compound. The product was purified by chromatography on a gradient of dichloromethane / ethyl acetate (1: 0 to 1: 1). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-4-methylphenylcarbamoyl) -pyrrolidine 4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained. NMR (DMSO-d ₆ + CD ₃ COOD): 1.19 (d 6H.), 1.92 (br, partially obscured, IH). 2.48 (s.

3H), 2.79 (broad, 1H), 3.25 (dd, 1H). 3.32 (i.e. 1H.

3.54 (quintet, 1H), 3.91 (broad m, 1H). 4.01 (quintet, 1H), 4.12 (dd, 1H), 4.25 (dd, 1H), 4.45 (m. 1H). 4.50-4.68 (m, 4H). 4.78 (dt. 2H), 5.18-5.45 (m, 6H), 5.70-6.13 (overlapping m and broad 3H), 7.25 (d. 1H), 7.76 (dd, 1H) ), 8.12 (broad, 1H);

Mass Spectrum (+ FAB): 654 (MH +, 676 (M + N

Example 31 FlR.5S.6S.8R, 2'S.4'S) -2- (2- / 3-Carboxy-5-methylphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) Preparation of -1-methylcarbapenem-3-carboxylic acid disodium salt g (4.59 mmol) (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3 - (Allyloxycarbonyl-5-methylphenylcarbamoyl) -pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester and 3.97 2,2-Dimethyl-1,3-dioxane-4,6-dione (27.6 mmol) was dissolved in a mixture of dimethylsulfoxide (15 mL) and tetrahydrofuran (5 mL) under argon, and tetrakis (531 mg, 0.46 mmol) was added. Triphenylphosphine) palladium was added and the solution was stirred under argon for 1 hour, protected from light by addition of 1.53 g (9.22 mmol) of sodium salt of 2-ethylhexanecarboxylic acid in 5 ml of tetrahydrofuran and 250 ml of the mixture. The precipitate was filtered off under argon to remove moisture, and then two portions of tetrahydrofuran were added. l.

Finally, wash with diethyl ether. The crude product and 1.5 g of sodium bicarbonate were dissolved in 100 ml of water and chromatographed on HP20SS resin. The eluent was gradient water to acetonitrile (10: 0 to 9: 1). It is combined with the appropriate eluate fraction and freeze-dried. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-methyl-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1- methyl carbapenem-3-carboxylic acid disodium salt is obtained.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.13 (d, 3H.). 1.15 (d, 3H). 1.76 (dt, 1H), 2.32 (s, 3H).

2.68 (dt. 1H). 2.87 (dd, 1H), 3.18 (dd, 1H). 3.36 (quintet 1H), 3.45 (dd 1H). 3.71 (quintet, 1H), 3.95 (quintet, 1H), 4.02 (t, 1H), 4.14 (dd, 1H), 7.49 (s, 1H), 7.65 (s, 1H) ), 8.05 (s, 1H);

Mass Spectrum (+ FAB): 512 (MH) ⁺ Monosodium salt, 534 (MH) ⁺ Disodium salt. 556 (M + Na) ⁺ disodium salt. The starting materials were prepared as follows:

Preparation of 3-methyl-5-nitrobenzoic acid g (0.198 mol) of 3,5-dimethyl-nitrobenzene. A mixture of 400 ml of pyridine and 250 ml of water was heated to 80 ° C with stirring. To the mixture in installments. Potassium permanganate (62.7 g, 0.396 mol) was added over 0.75 hours and the mixture was heated at 85-90 ° C for 1.75 hours. The solution is filtered hot through celite and the filter cake is washed with 150 ml of hot water. The pink filtrates were decolorized with a few drops of sodium metabisulfite solution. and then evaporate the volatiles. The residue was dissolved in water (250 mL) and the solution was extracted twice with 20 µl of diethyl ether. The aqueous phase was acidified with concentrated aqueous hydrochloric acid and extracted with ethyl acetate (3 x 120 mL). The organic extracts were combined, washed with aqueous sodium dihydrogen phosphate and brine, and dried over anhydrous magnesium sulfate. The crude product was purified by filtration through a pad of silica gel eluting with ethyl acetate / dichloromethane / acetic acid (25: 25: 1). 14.5 g (40%) of 3-methyl-5-nitrobenzoic acid are obtained; mp 171-172 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-d6): 2.51 (s, 3H), 8.17 (s. 1H), 8.30 (1H), 8.42 (t. 1H), 13.58 (broad 1H);

Mass spectrum (CI): 181 (MH) ^&lt; ^{+ &gt};.

3-Melyl-5-nitrobenzoic acid was allylated as described in Example 1. 3-Methyl-5-nitrobenzoic acid allyl ester is obtained, which is sufficiently pure for work-up without chromatography.

Nuclear Magnetic Resonance Spectrum (CDCl3: 2.53 (s, 3H). 4.87 (dt, 2H). 5.31-5.48 (m, 2H); 5.99-6.13 (m. 1H); , 20 (s, 1H) 8.23 (s. 1H), 8.68 (s. 1H):

Mass Spec (Cl): 222 (MH) ⁺ .

This nitro compound is reduced as described in Example 1. An allyl ester of 5-amino-3-methylbenzoic acid is obtained which is sufficiently pure for work-up of the horse without chromatography.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.20 (s, 3H), 3.46 (br. 2H), 4.78 (dt, 2H), 5.23-5.45 (m. 2H).

5.93-6.12 (m, 1H), 6.68 (t. 1H), 7.17 (t, 1H), 7.27 (t, 1H);

Mass Spec (Cl): 192 (MH) ⁺ , 220 (M + C ₂ H ₅ ) ⁺ .

This amine compound is condensed with proline carboxylic acid as described in Example 4. The product was purified by chromatography, eluting with hexane / ethyl acetate (3.1% by volume).

(2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / 5-methylphenylcarbamoyl) pyrrolidin-4-ylthioacetate.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.33 (s, 3H). 2.39 (s.

3H), 2.58 (br. 2H), 3.29 (dd, 1H), 4.02 (quintet).

IH). 4.13 (dd, 1H), 4.56 (t, 1H), 4.68 (dm, 2H).

4.82 (dt, 2H), 5.23-5.44 (m, 4H), 5.86-6.12 (m.

2H), 7.63 (s. 1H), 7.85 (s, 1H), 7.85 (s, 1H). 9.09 (broad 1H);

Mass Spectrum (+ FAB): 447 (MH +).

This thioacetal compound was deacetylated as described in Example I and then condensed with the caraphenem phosphate compound. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate (3: 2 to 2: 3). (IR.5S.6S.8R, 2'S.4'S) -2- (1- (Allyloxycarbonyl) -2- (37allyloxycarbonyl) -5-methylphenylcarbamoyl) -pyrrolidin-4-yl-lio) ] -6- (1-Hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester NMR (CDCR): 1.23 (d, 3H), 1.35 (d.

3H), 2.38 (s. 3H), 2.63 (broad 2H). 3.23 (dd. 1H).

3.27 (quintet 1H). 3.46 (broad 1H). 3.78 (quintet 1H), 4.00 (dd 1H). 4.24 (overlapping m. 2H). 4.51 (t. 1H). 4.59-4.63 (m. 4H |. 4.79 (d, 2H). 5.17-5.42 (m. 6H). 5.82-6.09 (m. 3H). 7.61 (s, 1H). 7.73 (s. 1H) 7.99 (s. 1H), 8.87 (broad, 1H);

Mass Spectrum (+ FAB): 654 (MH) ⁺ .

Example 32 (JR, 5S, 6S, 8R, 2'S, 4'S> -2-2- (3-Carboxy-5- (methoxycarbonyl) -phenylcarbamoyl) -pyrrolidinyl-4-yl-thiol-6-hydroxy) ethyl) -1-methylcarbapenem-3-carboxylic acid disodium salt

This compound was prepared as described in Example 2. except that dimethylformoxide is used instead of dimethylformamide.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.18 (d 6H.), 1.92, 2.81 (m (br, IH partially obscured.).

1H), 3.03 (dd, 1H), 3.23 (dd, 1H), 3.41 (quintet.

1H), 3.61 (m. 1H), 3.90 (overlapping s and m, 4H). 4.00 (quintet, 1H), 4.21 (overlapping m, 2H), 8.25 (ι. 1H).

8.50 (m, 2H);

Mass Spectrum (+ FAB): 556 (MH) ⁺ Monosodium salt.

578 (MH) ⁺ disodium salt.

The starting materials were prepared as follows:

3- (Methoxycarbonyl) -5-nitrobenzoic acid is allylated as described in Example 1. Allyl 3- (methoxycarbonyl) -5-nitrobenzoic acid is obtained which does not require chromatographic purification.

NMR _(DMSO-d6): 3.97 (. S, 3H). 4.91

HU 211840 A9 (dt, 2H), 5.31-5.51 (m, 2H), 6.00-6.19 (tn, 1H).

8.75 (t, 1H). 8.81 (d. 2H);

Mass spectrum (EI): 265 (M &lt; ⁺ &gt;).

This nitro compound was reduced as described in Example 2 except that methanol was used as the solvent. 3-Amino-5- (methoxycarbonyl) -benzoic acid allyl ester is obtained which is sufficiently pure for further conversion without chromatography. NMR _(DMSO-d6): 3.79 (br, 2H);

3.92 (s. 3H), 4.82 (dl, 2H), 5.26-5.46 (m, 2H),

5.94-6.14 (m, 1H), 7.53 (m, 2H), 8.07 (t 1H);

Mass spectrum (CI) 236 (MH) ⁺ , 253 (M + NH ₄ ) ⁺ .

This amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (10: 0 to 9: 1).

(2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / 5-methoxycarbonyl-phenylcarbamoyl) -pyrrolidin-4-ylthioacetal.

Nuclear Magnetic Resonance Spectrum (CDCl3): 2.33 (s. 3H), 2.60 (br. 2H). 3.40 (dd, 1H), 3.94 (s. 3H), 4.04 (quintet. 1H), 4.14 (dd, 1H), 4.58 (t. 1H). 4.68 (dm, 2H). 4.85 (dt. 2H). 5.25-5.47 (m. 4H),

5.85-6.16 (m. 2H). 8.36 (t, 1H), 8.43 (m, 2H). 9.40 (broad 1H):

Mass Spectrum (+ FAB): 491 (MH) ⁺ . 513 (M + Naf.

1.2 g (2.4 mmol) of (2S, 4S) -1- (allyloxycarbonyl) -213- (allyloxycarbonyl) -5- (methoxycarbonyl) phenylcarbamoyl) pyrrobdin-4-yl To a solution of thioacetate in 50 ml of telrahydrofuran was added 0.51 g of a 33% (w / v) aqueous solution of methylamine (5.4 mmol of methylamine) under argon. The reaction mixture was stirred for a further 3 hours and then the solvent was removed. To the residue was added 2N aqueous hydrochloric acid and the mixture was extracted with ethyl acetate. The organic extract was washed with water, aqueous sodium chloride solution and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. 1.02 g (93%) of (2S, 4S) -1- (allyloxycarbonyl) -2- (3- (allyloxycarbonyl) -5- (methoxycarbonyl) phenylcarbamoyl) pyrrolidine- 4-yl-thiol is obtained. This compound was condensed with the carbapenem phosphate compound as described in Example 1 without further purification. The product was purified by chromatography on a gradient of dichloromethane / ethyl acetate (1: 0 to 1: 1). (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -5- (methoxycarbonyl) phenylcarbamoyl) Pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

Nuclear Magnetic Resonance Spectrum (CDCl3): 1.24 (d, 3H), 1.37 (d, 3H), 2.64 (broad, 2H), 3.26 (overlapping dd and quintet, 2H), 3, 48 (broad, 1H), 3.86 (quintet, 1H), 3.94 (overlapping s and m, 4H), 4.25 (quintet, 1H), 4.29 (dd, 1H). 4.56 (t, 1H), 4.69 (m, 4H), 4.86 (dm, 2H), 5.19-5.46 (m, 6H), 5.85-6.13 (m, 3H), δ , 46 (m, 3H), 9.18 (br, 1H);

Mass Spec (+ FAB): 698 (MH) ⁺ , 720 (M + Na) ⁺ .

Example 33 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [5-Carboxy-2,4-difluorophenylcarbamoyl] -pyrrolidin-4-yl-thio) -6 - (} - Preparation of hydroxyethyl) -1-methylcarbapenet-3-carboxylic acid disodium salt

This compound was prepared as described in Example 2.

NMR _(DMSO-d6 + CD, COOD): 1.20 (d, 6H), 1.96 (m, partially obscured, IH), 2.81 (m, IH).

3.14 (dd, 1H), 3.27 (dd, 1H), 3.43 (quintet, 1H).

3.73 (m. 1H), 3.91 (quintet, 1H), 4.04 (quintet.

IH). 4.23 (dd, 1H), 4.43 (t, 2H), 7.29 (l, 1H). 8.54 (t, 1H);

Mass Spectrum (+ FAB): 534 (MH) * monosodium salt.

556 (MH) ⁺ disodium salt.

The starting materials were prepared as follows:

Preparation of 2,4-Difluoro-5-nitro-benzoic acid 2,4 gm (0.031 mol) of 2,4-difluoro-benzoic acid was prepared with 30 ml of concentrated sulfuric acid. 0 ° C while stirring. At a temperature below 5 ° C, 1.91 ml of a 1.567 g / ml solution of fuming nitric acid solution (0.047 molar nitric acid) was added dropwise. After stirring for 3 hours, the reaction mixture was poured onto ice and extracted with dichloromethane (2 x 75 mL). The organic extracts were combined. washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated. 3.9 g (61%) of 2,4-difluoro-5-nitrobenzoic acid are obtained. NMR _(DMSO-d6): 18.07 (. T, 1H). 8.88 (t, 1H), 9.93 (broad 1H);

Mass Spectrum (-FAB): 202 (M-H) -.

2.4-Difluoro-5-nitrobenzoic acid was allylated as described in Example 1, except that the reaction was completed after 1.5 hours. Dimethylformamide is pretreated with IR-120-H ion exchange resin before use. Chromatographic purification of the Ions was unnecessary. 2,4-Difluoro-5-nitrobenzoic acid allyl ester is obtained.

NMR _(CDCl3): 4.88 (. Dt 2H). 5.315.50 (m, 2H), 5.93-6.13 (ni. 1H), 7.13 (t. 1H). 8.80 (dd. 1H);

Mass spectrum (EI): 265 (M &lt; ⁺ &gt;).

This nitro compound was reduced as described in Example 2, except that methanol was used as the solvent. 5-Amino-2,4-difluorobenzoic acid ester is obtained which is sufficiently pure for further conversion without chromatography.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 3.61 (broad, 2H). 4.81 (dt, 2H), 5.26-5.48 (m, 2H), 5.92-6.12 (m, 1H).

6.83 (l, 1H), 7.38 (dd, 1H);

Mass spectrum (CI): 214 (MH) ⁺ , 231 (M + NH ₄ ) ⁺ .

This amine compound is condensed with proline carboxylic acid as described in Example I. Its products are purified by chromatography, eluting with a gradient of dichloromethane / diethyl ether (10: 0 to 9: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2,4-difluorophenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. NMR (CDC1 _3): 2.33 s, 3H), 2.63 (szé31

HU 211 840 A9 les. 2H), 3.39 (dd, 1H), 4.04 (quintet, 1H), 4.14 (dd. 1H). 4.59 (ι, 1H), 4.66 (dl, 2H), 4.83 (dt, 2H), 5.22-5.49 (m, 4H), 5.84-6.13 (m, 2H) , 6.94 (t, 1H),

8.82 (t, 1H), 9.22 (broad, 1H);

Mass Spectrum (+ FAB): 469 (MH) ⁴ , 491 (M + Na) ⁺ . This thioacetate compound was deacetylated as described in Example 1 and then condensed with the carbapenem phosphate compound. The product was purified by chromatography on a gradient of dichloromethane / ethyl acetate (1: 0 to 1.1).

(LR, 5S, 6S, 8R, 2'S.4'S) -2- [l- (-allyloxycarbonyl) -2- (5 / allyloxy carbonyl / -2,4-difluorophenyl-carbamoyl) - Pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.25 (d, 3H). 1.38 (d, 3H). 2.62 (broad, 2H); 3.24 (overlapping dd and quintet, 2H). 3.45 (dd. 1H), 3.88 (quintet, 1H), 4.03 (dd, 1H). 4.25 (quintet, 1H). 4.29 (dd. 1H). 4.57 (t. 1H).

4.68 (m. 4H>. 4.82 (dm. 2H). 5.21-5.48 <m. 6H).

5.85-6.10 (m. 3H). 6.94 (t. 1H). 8.85 (ι, 1H), 9.12 (broad, 1H);

Mass Spectrum (+ FAB): 676 (MH) ⁴ , 698 (M + Na) ⁴ .

Example 34 tR5S.6S.8R.2'S.4'S) -2-1,2- (5-Carboxy-2,4-dioxyethyl-phenylcarbamoyl / -pyrrolidin-4-yl-thio) -6- (1 Preparation of -hydroxyethyl) -1-methylcarbapel-3-carboxylic acid

This compound was prepared as described in Example 2.

NMR (DMSO-d ₆ + CD ₃ COOD): 1.20 (d 6H.). 1.95 (m. Partially distorted. IH). 2.87 (dt. 1H). 3.08 (dd. 1H). 3.26 (dd. 1H). 3.41 (quintet 1H), 3.71 (dd 1H). 3.87 (quintet, partially distorted, IH),

3.91 (s. 3H). 3.96 (s, 3H). 4.03 (quintet, 1H). 4.21 Idd. IH). 4.39 (t. 2H). 6.76 (s, 1H). 8.44 (s, 1H);

Mass Spectrum (+ FAB): 558 (MH) monosodium salt. 580 (MH) ⁴ disodium salt.

The starting materials were prepared as follows:

Preparation of 2.4-Dinethoxy-5-yl-nitrobenzoate

1.42 g (0.062 mol) of metal sodium are dissolved in 40 ml of methanol under cooling. To the resulting sodium methoxide solution was added 5 g (0.021 mol) of allyl 2,4-difluoro-5-nitrobenzoic acid and the mixture was stirred for 2 hours. A solution of sodium hydroxide (2 g, 0.05 mol) in water (10 ml) was added and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated, the residue was dissolved in water (50 ml) and the aqueous solution was washed with diethyl ether (40 ml). The aqueous phase is acidified with sulfuric acid and the precipitate is filtered off and dried. 4.23 g (91%) of 2,4-dimethoxy-5-nitrobenzoic acid are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): 4.07 (s, 3H), 4.16 (s,

3H), 6.62 (s, 1H). 8.81 (s, 1H);

Mass Spectrum (Cl): 228 (MH) ⁴ , 245 (M + NH ₄ ) ⁴ .

2.4-Dimethoxy-5-nitrobenzoic acid is allylated as described in Example I. 2,4-Dimethoxy-5-nitrobenzoic acid allyl ester is obtained; no chromatographic purification of the product is required.

Nuclear Magnetic Resonance Spectrum (CDC13): 4.02 (s, 3H). 4.04 (s.

3H), 4.79 (dl. 2H), 5.26-5.46 (m, 2H), 5.93-6.13 (m, 1H). 6.54 (s. 1H); 8.63 (s, 1H);

Mass Spectrum (+ FAB): 268 (MH) ⁴ . 290 (M + Na) ⁴ .

This nitro compound is reduced as described in Example 1. The allyl 5-amino-2,4-dimethoxybenzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 3.25 (br, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 4.76 (dt, 2H), 5.22-5.46 (m.

2H), 6.12-5.93 (m, 1H), 6.47 (s, 1H), 7.29 (s, 1H): Mass Spectrum (Cl): 238 (MH) ⁴ .

The amine compound thus obtained is condensed with proline carboxylic acid as described in Example 4. The product was purified by chromatography eluting with dichloromethane: diethyl ether (10: 0 to 4: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (5- (allyloxycarbonyl) -2,4-dimethoxy] methylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDC13): 2.32 (s, 3H), 2.49 (broad 1H). 2.64 (broad 1H). 3.40 (dd. 1H). 3.91 (s, 3H). 3.93 (s, 3H), 4.00 (quintet, 1H). 4.17 (dd.

1H), 4.53 (t. 1H). 4.64 (d, 2H), 4.77 (dt. 2H |.

5.19-5.46 (m. 4H), 5.80-6.14 (m. Broad overlapping).

2H), 6.49 (s. 1H). 8.69 (broad, 1H). 8.81 (s. 1H); Mass Spectrum (+ FAB): 493 (MH) ⁴ .

The thioacetate compound thus obtained was deacetylated and condensed with carbapenem phosphate as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyl) in pure dichloromethane to pure ethyl acetate. oxycarbonyl) -2- (5-allyloxycarbonyl-2,4-dimethoxyphenylcarbamoyl) pyrrolidin-4-ylthio] -O- (1-hydroxyethyl) -1-methylcarboxylic acid allyl-carboxylic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.22 (d, 3H). 1.36 (d.

3H). 2.48 (broad 1H), 2.65 (broad 1H). 3.23 (dd.

IH). 3.28 (quintet, 1H), 3.43 (dd, 1H). 3.80 (quintet, 1H), 3.91 (s, 3H), 3.92 (s. 3H), 4.09 (dd. 1i).

4.24 (quintet, 1H), 4.27 (dd. 1H). 4.51 (t. 1H). 4.66 (m. 4H). 4.77 (d1, 2H). 5.20-5.45 (m, 6H). 5.836.11 (overlapping m and broad, 3H); 6.49 (s, 1H). 8.45 (broad, 1H), 8.82 (s, 1H);

Mass Spectrum (FAB): 700 (MH) ⁴ .

Example 35 (IR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [5-Carboxy-2-cyano-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- ( ! hydroxyethyl) - Preparation of the di-triethyl salt of methylcarbapenem-3-carboxylic acid

This compound was prepared as described in Example 2. except that dimethylformamide is replaced by dimethylsulfoxide.

NMR _(DMSO-D6 + CDjCOOD): 1.17 (d, 6H). 1.83 (m, partially distorted, 1H), 2.62-2.79 (overlapping m. 2H), 3.18 (dd, 1H), 3.41 (quintet, 1H).

HU 211 840 A9

3.66 (quintet, 1H), 3.98 (quintet, 1H), 4.07 (dd, 1H), 4.17 (dd, 1H), 7.79 (m, 2H), 8.67 (s) , 1H);

Mass Spectrum (+ FAB): 523 (MH) * monosodium salt, 545 (MH) ⁺ disodium salt.

The starting materials were prepared as follows:

Preparation of 4-Cyano-3-nitro-benzoic acid

4-Chloro-3-nitrobenzoic acid (5.84 g, 29 mmol); Copper (I) cyanide (5.2 g, 58 mmol). A mixture of copper (I) chloride (0.96 g, 9.7 mmol) and quinoline (6.9 mL, 58 mmol) was heated at 180 ° C for 3.5 h under argon. The reaction mixture was cooled, dissolved in concentrated aqueous hydrochloric acid (60 mL), diluted with water (80 mL), and extracted with ethyl acetate (3 x 100 mL). The organic phases are combined, washed with aqueous sodium dihydrogen phosphate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The isolated crude product was purified by chromatography on silica gel eluting with dichloromethane: acetic acid (98: 2). Yield: 2.65 g (489f) of 4-cyano-3-nitrobenzoic acid.

NMR _(DMSO-d6): 8.31 (d, IH), 8.41 (dd MA.), 8.68 (d IH.);

Mass Spectrum (EI): 192 (M ⁺ ).

This carboxylic acid was reduced as described in Example 1. The crude product was purified by chromatography on silica gel eluting with hexane / ethyl acetate (6: 1). 4-Cyano-3-niobenzoic acid allyl ester is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.93 (dt. 2H), 5.375.50 (m. 2H). 5.97-6.13 (m, 1H), 8.03 (d. 1H), 8.46 (dd. 1H). 8.94 (d. 1H):

Mass Spec (Cl): 221 (MH) +, 250 (M + NH ₄ ) ⁺ .

This nitro compound is reduced as described in Example 1. 3-Amino-4-carbamoylbenzoic acid allyl ester is obtained, which is recrystallized from ethyl acetate / petrol melting at 149-150 ° C.

NMR _(DMSO-d6): 4.77 IDT, 2H). 5.25-5.43 (m. 2H), 5.96-6.11 (m, 1H), 6.72 (broad, 2H). 7.04 (dd. 1H). 7.25 (broad, 1H). 7.35 (d, 1H), 7.63 (d, 1H). 7.87 (broad, 1H);

Mass Spectrum (EI): 220 (M +).

This amine compound is serinically condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography eluting with ethyl acetate / hexane (1: 1).

(2S, 4S) -1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl / 2-carbamoylphenylcarbamoyl) -pyrrolidin-4-ylthioacetate.

Nuclear Magnetic Resonance Spectrum (CDCl3, mixture of rotamers):

2.25 (quintet, 1H), 2.28 (s, 3H), 2.82 (broad, 1H),

3.52 (dd, 1H). 4.13 (t, 1H), 4.20 (broad m, 1H),

4.52 (dd, 1H), 4.61 (broad, 2H), 4.85 (d, 2H), 5.01-5.48 (overlapping m and broad, 4H), 5.66-6.12 (overlapping) m and broad, 2H), 6.55 (broad, 1H), 6.89 (broad, 1H). 7.64 (br m, 1H), 7.79 (br m, 1H), 9.30 (br m, 1H). 11.68 (br, 0.5H), 12.06 (br, 0.5H);

Mass Spectrum (+ FAB): 476 (MH +).

Preparation of (2S, 4S) -1- (Allyloxycarbonyl) -2- (5-allyloxycarbonyl-2-cyanophenylcarbamoyl) pyrrolidin-4-ylthioacetate

To a solution of dimethylformamide (0.2 mL, 2.5 mmol) in acetonitrile (10 mL) at -5 ° C was added oxalyl chloride (0.2 mL, 2.3 mmol). The mixture was stirred for 30 minutes and then 1 g (2.1 mmol) of (2S, 4S) -1- (allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2-carbamoylphenylcarbamoyl) -pyrrolidine A solution of -4-ylthioacetate in acetonitrile (15 mL) was added pyridine (0.38 mL, 4.6 mmol), and after 15 minutes the reaction mixture was diluted with ethyl acetate (200 mL), 2N aqueous hydrochloric acid (20 mL), The crude product was purified by chromatography, eluting with a gradient gradient of dichloromethane / ethyl from pure dichloromethane to pure ethyl acetate. 0.9 g (93%) of (2S, 4S) -1- (allyloxycarbonyl) -2- (5-allyloxycarbonyl / -2-cyanophenylcarbamoyl) pyrrolidine were used. -4-ylthioacetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.32 (s, 3H), 2.63 (broad, 2H), 3.46 (dd, 1H), 4.06 (quintet, 1H). 4.16 (dd, 1H) , 4.64 (t, 1H), 4.71 (dt, 2H), 4.85 (dt, 2H).

5.22-5.47 (m. 4H), 5.87-6.14 (m. 2H). 7.67 (d.

IH). 7.87 (dd. 1H). 8.96 (d. 1H). 9.42 (broad 1H): mass spectrum (+ FAB): 458 (MH) ⁺ . 480 (M + Na) ⁺ .

This thioacetate compound was deacetylated and condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [1- (Allyl) in pure dichloromethane to pure ethyl acetate. oxycarbonyl) -2- (3-allyloxycarbonyl / -2-methoxyphenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem An allyl -3-carboxylic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 1.24 (d, 3H). 1.35 (d.

3H), 2.60 (broad, 2H). 3.25 (overlapping dd and quintet.

2H), 3.52 (broad, 1H), 3.88 (quintet, 1H), 4.02 (dd.

1H), 4.25 (quintet. 1H), 4.28 (dd. 1H). 4.55-4.74 (m, 5H), 4.85 (dt, 2H), 5.18-5.468 (m, 6H). 5.836.11 (m, 3H), 7.65 (dt, 1H), 7.87 (dd, 1H). 9.00 (s broad, 1H), 9.25 (broad s, 1H);

Mass Spectrum (+ FAB): 665 (MH) ⁺ , 687 (M + Na) ⁺ .

Example 36 (1R, 5S, 65,8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-fluoro-phenylcarbanoyl] -pyrimidin-4-yl-thio) -6-yl- Preparation of Hydroxyethyl) -1-Methyl-Carbapenem-3-Carboxylic Acid

This compound was prepared as in Example 2 except that dimethylsulfoxide was used in place of dimethylformamide.

Nuclear Magnetic Resonance Spectrum (DMSO-d6 + CD3COOD): 1.20 (d,

6H), 1.99 (dt, 1H), 2.91 (dt, 1H), 3.26 (dd and m, overlapping)

3H), 3.42 (quintet, 1H), 3.74 (dd. 1H), 3.96 (quintet.

1H), 4.04 (quintet, 1H), 4.22 (dd, 1H). 4.41 (t. 1H).

7.43 (dm, 1H), 7.81 (dd, 1H), 8.00 (t, 1H); Mass Spec (+ FAB): 516 (MH) * monosodium salt,

538 (MH) * disodium salt.

HU 211 840 A9

The starting materials were prepared as follows:

Preparation of 3-Fluoro-5-nitrobenzoate

Prepare a suspension of 3.53 g (30.2 mmol) of nitrosonium tetrafluoroborate in 50 ml of acetonitrile under argon. under ice-cooling and vigorous stirring, 3-amino-5-nitrobenzoic acid (5.0 g, 27.5 mmol) was added in three portions. The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. To the mixture was added 1,2-dichlorobenzene (50 ml) and the acetonitrile was distilled off under reduced pressure. The residue was heated at 170 ° C for 30 minutes; then gas evolution is complete. The mixture was cooled, poured into dichloromethane (200 mL) and extracted with aqueous sodium bicarbonate. The aqueous phase was washed with dichloromethane. It is acidified with 2N aqueous hydrochloric acid and then extracted with twice 100 ml of ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The crude product obtained is purified by chromatography on silica gel using a gradient gradient solvent mixture of dichloromethane: acetic acid (99: 1) to dichloromethane: isopropanol: acetic acid (80: 80: 1). 3.26 g (64%) of 3-fluoro-5-nitrobenzoic acid are obtained. NMR _(DMSO-D6): 8.14 (dm, MA.).

8.37 (dl. 1H). 8.46 (m. 1H):

Tomegspektrum {Eli: 185 {MD.

Preparation of 3-Fluoro-5-yl-benzobenzoic allyl ester A mixture of 3-fluoro-5-nitrobenzoic acid (16.2 mmol), p-toluenesulfonic acid (1.54 g, 8.1 mmol) and allyl alcohol (50 mL) was stirred for 16 hours. refluxing; the distillate is passed through a 3 mesh sieve. The reaction mixture was cooled and neutralized with triethylamine. and evaporating the solvent. The residue was dissolved in ethyl acetate, washed with 2N aqueous hydrochloric acid, aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The crude product was purified by chromatography on silica gel eluting with a gradient gradient of dichloromethane: ethyl acetate (10: 0 to 3: 1). Allyl 3-Fluoro-5-nitrobenzoic acid is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3): 4.89 (dt, 2H), 5.335.49 (m, 2H). 5.95-6.15 (m, 1H). 8.11 (m, 2H).

8.70 (1H);

Mass spectrum (CI): 226 (MH ⁺ ). 253 (M + C ₂ H ₅ ) ⁺ .

This nitro compound is reduced as described in Example 1. 3-Amino-5-fluorobenzoic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 3.89 (broad, 2H), 4.79 (dt. 2H), 5.25-5.45 (m, 2H), 5.92-6.12 (m, 1H).

6.54 (dt. 1H). 7.07-7.15 (m, 2H):

MS (Cl): 196 (MH) ^&lt; ^{+ &gt};.

This amine compound was condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography eluting with dichloromethane: diethyl ether (100: 0 to 85:13, v / v). (2S, 4S) -1- (Altyloxycarbonyl) -2- (3- (allyloxycarbonyl) -5-fluorophenylcarbamoyl) pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDC13): 2.33 (s, 3H). 2.59 (broad, 2H). 3.48 (dd, 1H), 4.03 (quintet, 1H). 4.13 (dd, 1H), 4.56 (t. 1H), 4.68 (dt, 2H), 4.82 (dt, 2H). 5.25-5.46 lm, 4H), 5.86-6.11 (m, 2H), 6.47 (dm. 1H), 7.72 (t, 1H), 7.87 (dt m, 1H), 9.38 (broad, 1H);

Mass Spectrum (+ FAB): 451 (MH) ⁺ , 473 (M + Na) ⁺ . This lyoacetate compound was deacetylated and condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography eluting with a gradient gradient of dichloromethane / ethyl acetate from pure dichloromethane to pure ethyl acetate. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl / -5-fluorophenylcarbamoyl) pyrrolidine4 allyl thio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13) 1.24 (d, 3H), 1.36 (d, 3H). 2.63 (br. 2H). 3.26 (dd. 1H). 3.29 (quintet, 1H). 3.48 (broad I), 3.81 (quintet, 1H). 3.97 (dd. 1H). 4.27 (overlapping dd and m, 2H), 4.54 (t, 1H). 4.624.76 (m. 4H). 4.81 (dt. 2H). 5.20-5.46 (m. 6Hi.

5.85-6.10 (overlapping m and broad 3H); 7.48 (dt. 1H).

7.83 (broad s. 1H). 7.88 (dl, 1H). 9.18 (broad 1H):

Mass Spectrum (+ FAB): 658 (MH) ⁺ . 680 (M + NaT.

Example 37 R5S.6S.8R.2'S.4'S) -2- [2- (3-Carboxy-N'-phenyl-phenylcarbonyl) -pyrrolidin-4-yl] -6- Preparation of (N-Hydroxy-Er) -J-Methylcarbapenern-3-Carboxylic Acid (dii) Remunium Salt

This compound was prepared as described in Example 2. except that dimethylsulfoxide is used in place of dimethylformamide. The product was purified by chromatography on a CHP20P column eluting with water.

NMR _(DMSO-d6 + CDjCOOD at 50 ° C.): 1.12 (d 3H.). 1.18 (d, 3H), 1.67 (br, 1H, 2.13 (br, 1H, 3.22 (dd, 1H)), 3.17 (dd, 1H). 3.28 (overlapping s and m. 5H), 3.65 (broad, 1H), 3.98 (overlapping quintet and m. 2H), 4.12 (dd, 1H), 7.58 (d. 1H), 7.91 (d, 1H), 7.98 (m. 1H);

Mass Spectrum (+ FAB): 512 (MH) ⁺ Monosodium salt. 534 (MHt * disodium salt.

The starting materials are prepared as follows:

Preparation of allyl 3- (methylamino) benzoic acid To a solution of allyl 3-aminobenzoic acid (5 g, 28.2 mmol) in triethyl ortho-acetic acid is added 5 drops of trifluoroacetic acid. The solution was heated to reflux for 5 hours with stirring; the distillate is passed through a molecular sieve of 3 Å pore size. The solvent was evaporated and the residue was dissolved in 50 ml of ethanol. To the solution was added 8.08 ml of acetic acid, followed by 6.85 g (0.108 mol) of sodium cyanoborohydride in several portions. The mixture was stirred at room temperature for 16 hours

After stirring, the solvent was evaporated. The residue was dissolved in diethyl ether, washed with water and brine, and dried over anhydrous magnesium sulfate. The crude product was purified by chromatography on silica gel using dichloromethane: ethyl acetate (100: 0 and 95: 5 gradient gradient). 0.93 g (17%) of allyl 3-methylamino-benzoic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDC13): 2.88 (s, 3H), 4.81 (dt, 2H), 5.23-5.45 (m, 2H), 5.94-6.13 (m, 1H). ), 6.83 (dd, 1H), 7.25 (dd, 1H), 7.33 (t, 1H), 7.43 (dm, 1H);

Mass Spec (Cl): 192 (MH) ⁺ .

This amine compound is condensed with proline carboxylic acid as described in Example 1. The product was purified by chromatography on a gradient of dichloromethane / diethyl ether (10: 0 to 4: 1). (2S, 4S) -1- (Allyloxycarbonyl) -2- (3-allyloxycarbonyl-N'-melylphenylcarbamoyl) -pyrrolidin-4-ylthioacetate is obtained. Nuclear Magnetic Resonance Spectrum (CDCl3, mixture of rotamers):

1.93 (m. 1H). 2.32 (s. 3H). 2.48 (m. Partially distorted. IH). 3.28. 3.31 (2xs. 3H), 3.40 (quintet 1H). 3.76 (m. 1H). 4.01 (m. 1H). 4.24 (m. 1H). 4.50-4.74 (m. 2H). 4.86 (d. 2H). 5.18-5.48 (m. 4H). 5.84-6.13 tm. 2H. 7.38-7.68 (m. 2H). 7.90-8.11 (m. 2H);

Mass Spectrum (+ FAB): 447 (MH) ⁺ . 469 (M + Na) +. This thioacetate compound was deacetylated and condensed with the carbapenem phosphate compound as described in Example 1. The product was purified by chromatography, eluting with a gradient gradient of dichloromethane / ethyl acetate / pure dichloromethane to pure ethyl acetate. (1R.5S.6S.8R.2'S.4'S) -2- [1- (Allyloxycarbonyl) -2- (3- (Allyloxycarbonyl) -N'-methylphenylcarbamoyl) - Pyrrolidin-4-ylthio] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid allyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl 3, Rotamer mixture):

1.20 (2xd. 3H). 1.34 (2xd. 3H). 1.87 (broad 1H), 2.30 (broad 1H). 3.29, 3.31 (2xs and overlapping m. 6H). 4.05-4.30 (m. 4Hl. 4.50-4.81 (m, 5Hi. 4.96 (d, 2H). 5.20-5.48 (m. 6H), 5.85-6.13 (m, 3H)) 7.397.68 (m, 2H) 7.91-8.11 (m, 2H);

Mass Spectrum (+ FAB): 654 (MH) *, 676 (M + Na) *.

Claims (21)

PATENT CLAIMS Compounds of formula I, their pharmaceutically acceptable salts and esters which can be hydrolysed in vivo, wherein: R ^{1 is} 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl. R ^{2 is} hydrogen or C 1-4 alkyl. R 'is hydrogen or C 1-4 alkyl. and R ⁴ and R ⁵ are independently hydrogen. halogen, cyano, C 1-4 alkyl. nitro. hydroxy, carboxyl, C 1-4 alkoxy. (C1-C4) alkoxy-carbonyl, amino-sulfonyl, (C1-C4-alkyl) -amino-sulfonyl, di (C1-C4-alkyl) -amino-sulfonyl, carbamoyl, (1-4) C 1-4 alkylcarbamoyl, di-C 1-4 alkylcarbamoyl, trifluoromethyl. sulfonic acid, amino, (C1-C4 alkyl) amino, di (C1-C4 alkyl) amino, (C1-C4 alkanoyl) amino, (C1-C4 alkanoyl) - (N (C 1 -C 4 alkyl) -N-amino or C 1 -C 4 alkanesulfonamido or (C 1 -C 4 alkyl) -S (O) _n - wherein n is 0, 1 or 2, with the proviso that there is no hydroxyl or carboxyl substituent attached to the phenyl ring at the ortho position relative to the -NR 'linkage. Compounds of formula (I) according to claim 1, wherein R ^{1 is} 1-hydroxyethyl. Compounds of formula (I) according to claim 1 or 2, wherein R ^{2 represents a} hydrogen atom or a methyl group. Compounds of formula (I) according to claim 1 or 2. wherein ^R is methyl. 5. Compounds of formula (I) according to any one of claims 1 to ³ , wherein R ^{3 is} hydrogen. 6. Compounds of general formula (IV) which are a narrow group of compounds according to any one of claims 1 to ⁵ , wherein R ³ , R ⁴ and R ⁵ are as defined in claims 1-5. A process as claimed in any one of claims 1 to 6. Compounds of formula IV according to claim 6, wherein R ⁴ and R ⁵ are independently hydrogen, fluorine. chlorine or hydroxyl. carboxyl. cyano. nitro, methyl. ethyl, methoxy. ethoxy. methoxycarbonyl. carbamoyl. methylcarbamoyl. dimethylcarbamoyl, trifluoromethyl, sulfonic acid. methylsulfinyl, methylsulfonyl, methanesulfonamido or acetamido. Compounds of formula (IV) according to claim 6 or 7, wherein at least one of R ⁴ and R ⁵ is hydrogen. Compounds of formula IV according to claim 6, wherein R ^{4 is} hydrogen, fluoro, chloro or carboxyl, methyl, methoxy. cyano. sulfonic acid or methoxycarbonyl; and R ⁵ is hydrogen. 10. Compounds according to claim 1, as follows: (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-hydroxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methylcarbapenem-3-carboxylic acid, (JR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-4-chloro-phenylcarbamoyl] -pyrrolidin-4-yl- 10o) -6- (1-Hydroxyethyl) -1-methyl 1-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6) -chlorophenylcarbamoyl (pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2 - (2- / 3-carboxyphenyl karbamo35 HU 211,840 Δ 9 η 5 -pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2′S, 4′S) - 2- [2- (3-Carboxy-6- (methanesulfonyl-phenylcarbamoyl) -pyrrolidin-4-yl-thio] -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3- carboxylic acid. (IR, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-4-fluorophenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6-fluoro-phenylcarbamoyl / -pyrrolidin-4-yl-thio) - 6- (1-Hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-2,4-difluoro- phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (l-hydroxyethyl) -lmelil-carbapenem-3-carboxylic acid, GR.5S.6S.8R.2'S.4'S) -2- (2- / 3,4-Dicarboxyphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methyl carbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-4-hydroxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-methyl-carbapenem-3-carboxylic acid. (1R.5S.6S.8R.2'S, 4'S) -2- (2- (3,5-Dicarboxyphenylcarbamoyl) pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) - 1-methyl-karbapeneni -? - carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4S) -2- (3-Carbamoyl-3-carboxyphenylcarbamoyl) -pyrrolidin-4-ylthio) -6- (1-hydroxy-ethyl) -] - methyl carbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3-Carboxy-4-carbamoyl-enyl-carbamoyl-pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) 1-methyl-carbapenem-3-carboxylic acid. () R.5S.6S.8R.2'S.4'S) -2- (2- / 3-Carboxy-5-carbamoylphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) ) -1-methylcarbapenem-3-carboxylic acid. 1R, 5S, 6S, 8R, 2S, 4'S) -2- [2- (3-Carboxy-5-acetamido-phenyl-carbamoyl) -pyrrolidin-4-yl-thio] -6- (1-hydroxy-ethyl) -1 methylcarbapenem-3-carboxylic acid. 1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-5-amido-phenyl-carbamoyl-pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1 methylcarbapenem-3-carboxylic acid. (LR.5S, 6S, 8R.2'S.4'S) -2- [2- (3-carboxy-5- / methyl-sulfonamido / phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (hydroxy ethyl) -l-methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-5-sulfo-phenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - l-methyl-carbapenem-3-carboxylic acid. <1R.5S.6S.8R.2'S, 4'S) -2- (2- / 3-Carboxy-6-carbamoylienylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) 1 methylcarbapenem-3-carboxylic acid. (IR.5S, 6S.8R.2'S.4'S) -2- [2- (3-carboxy-2- / dimethyl-aminocarbonyl / phenylcarbamoyl) pyrrolidin-4-ylthio] -6- (1H-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid. (5R.6S.8R.2'S.4'S) -2- (2- / 3-Carboxyphenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -carbapenic-3-carboxylic acid, ( 1R, 5S, 6S, 8R, 2'S, 4'S) -2- (273-Carboxy-4-methyl-phenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl- carbape non-3-carbonic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-5-methyl-phenylcarbamoyl / pyrrolidin-4-yl-thio) -6- (1-Hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3-carboxy-6-methyl-phenylcarbamoyl) 1 H -pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-2-methoxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-4-methoxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1-methyl -carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-methoxy-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- ( 1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-Carboxy-6-methoxy) phenylcarbamoyl (pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S.8R, 2'S, 4'S) -2- ( 2- [3-Carboxy-4,6-dimethoxymethylcarbamoyl] -pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbaperem-3-carboxylic acid, (1R, 5S .6S, 8R, 2'S, 4'S) -2- [2- (3-Carboxy-5-methoxycarbonyl-1'-phenylcarbamoyl) -pyrrole di η-4-ylthio] -6- ( 1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-5-cyanophenylcarbamoyl / pyrrole) idin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S, -2- (2/3) -carboxy-5- (trifluoromethyl) phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid. <1R.5S, 6S.8R.2'S.4'S) -2- (2- / 3-Carboxy-4,6-difluorophenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxy) ethyl 1-1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- [2- (3-carboxy-6- (methylsulfinyl) -phenylcarbamoyl) -pyrrolidine- 4-i] thio] -6- (1-hydroxyethyl) -1-melylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4S) -2- [2- (3-Carboxy-5-methylsulfonyl-phenylcarbamoyl) -pyrrolidin-4-yl] -J-6- (1-Hydroxyethyl) -1-melylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S.4'S) -2- (2- / 3-Carboxy-5-fluoro-phenylcarbamoyl) -pyrrolidine -4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- (3-Carboxy-6-cyano-phenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (IR, 5S.6S.8R.2'S.4'S) -2- (2- (3-Carboxy-N'-methyl-phenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, and pharmaceutically acceptable salts thereof. 11. Compounds according to claim 1, as follows: (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-methyl-phenylcarbanoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-5-meloxyphenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) - 1-bis-1-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-6-methoxy-phenylcarbamoyl] -pyrrolidin-4-yl] -thio) -6- (1-hydroxyethyl) -1-methylcarbapenetic acid-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy-5- (methoxycarbonyl) phenylcarbamoyl / pyrrolidin-4-ylthio) -6- (1-hydroxyethyl) -1-methyl-1-carbapenem-3-carboxylic acid. HU 211 840 A9 (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-5-cyanophenyl] cabamoyl] -pyrrolidin-4-yl-thio) -6- (1 -hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3-carboxy-6-chloro-phenylcarbamoyl) -pyrrolidine-4 -ylthio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3-carboxy) phenylcarbamoyl / pyrrolidin-4-yl-thiophene-6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- [3-Carboxy-4-fluoro-phenylcarbamoyl] -pyrrolidin-4-yl-thio) -6- (1-hydroxy-ethyl) -1 methylcarbapenem-3-carboxylic acid. (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- [3-Carboxy-6-fluoro-phenylcarbamoyl] -pyrrolidin-4-yl-lio) -6- (1-hydroxy-ethyl) - 1-Methyl-carbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- / 3,4-Dicarboxyphenyl-carbamoyl / -pyrrolidin-4-yl-thio) - 6- (1-Hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, (1R, 5S, 6S, 8R, 2S, 4'S) -2- (2- / 3,5-Dicarboxyphenylcarbamoyl) -pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid. <1R.5S.6S.8R.2'S.4'S) -2- (2- / 3-Carboxy-5-sulfophenylcarbamoyl / pyrrolidin-4-yl-thio) -6- (1-hydroxyethyl) ) -1-methylcarbapenem-3-carboxylic acid. and pharmaceutically acceptable salts of the listed compounds v. 12. A pharmaceutical composition, characterized by. 1-11. A compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. A process for the preparation of a compound according to claim 1. characterized in that a compound of formula V wherein R ^{2 is} . R ⁴ and R ^{5 represent} the groups listed in claim 1, wherein R ⁴ and R ⁵ may optionally carry a protecting group, -COOR ⁶ and -COOR a carboxyl group or a protected carboxyl group. R * represents a R ³ group according to claim 1 or an amino group protecting group and R ¹⁰ represents a R ¹ group according to claim ¹ , a protected 1-hydroxyethyl group or a protected hydroxymethyl group. and deploying at least one protecting group of the compound of formula (V) - and if necessary, (i) forming a pharmaceutically acceptable salt, (ii) esterifying it to a hydrolysable ester in vivo. 14. Compounds of formula (V) as defined in claim 13. 15. A process for the preparation of a compound according to claim 1 or a compound of formula V as defined in claim 13, characterized in that a) reacting a compound of formula VI with a compound of formula VIII wherein R ² and R ⁴ -R ¹⁰ are as defined in claim 13 and L is a leaving group, or b) a compound of formula VIII wherein R ² and R ⁴ -R ¹⁰ are as defined above, and R ¹² and R ¹³ are independently C 1-6 alkoxy, aryloxy. di- (C 1-6 alkyl) amino or diarylamino; or Any two of R, R ¹² and R ¹³ may together form an o-phenylene dioxo group, or R ¹¹ , R ¹² and R ^{13 are C} 1 -C 4 alkyl. allyl. benzyl or phenyl, and the remaining two groups are independently C 1-4 alkyl. trifluoromethyl or phenyl. and the phenyl groups in the listed groups are optionally substituted with C 1-3 alkyl or C 1-3 alkoxy. and any reactive group present in compound (VIII) may be optionally protected by a protecting group; and then, if necessary, (i) removing any protecting groups. (ii) forming a pharmaceutically acceptable salt: (iii) esterification to form a hydrolyzable ester as disclosed in vivo. 16. The pharmaceutically acceptable salts of the compounds of formula I according to claim 1 17. Compounds of formula (VII) and (VIII) as defined in claim 15. 18. Compounds of formula (IX), (XII) and (XIV): wherein R ² and R ⁴ -R ¹⁰ are as defined in claim 13 and R ^{14 is} protecting group. 19. New compounds. characterized in that they are essentially as described herein. 20. Novel pharmaceutical formulations characterized in that they are essentially as described herein. 21. A novel process for the preparation of compounds according to claim 1, characterized in that it is essentially as described herein.